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Review

Cite This: Chem. Rev. 2020, 120, 200−268 pubs.acs.org/CR

Photo- and Redox-Driven Artificial Molecular Motors Massimo Baroncini,*,†,‡ Serena Silvi,*,†,§ and Alberto Credi*,†,‡

† CLAN-Center for Light Activated Nanostructures, Istituto ISOF-CNR, via Gobetti 101, 40129 Bologna, Italy ‡ Dipartimento di Scienze e Tecnologie Agro-alimentari, Universitàdi Bologna, viale Fanin 44, 40127 Bologna, Italy § Dipartimento di Chimica “G. Ciamician”, Universitàdi Bologna, via Selmi 2, 40126 Bologna, Italy

ABSTRACT: Directed motion at the nanoscale is a central attribute of life, and chemically driven motor proteins are nature’s choice to accomplish it. Motivated and inspired by such bionanodevices, in the past few decades chemists have developed artificial prototypes of molecular motors, namely, multicomponent synthetic species that exhibit directionally controlled, stimuli-induced movements of their parts. In this context, photonic and redox stimuli represent highly appealing modes of activation, particularly from a technological viewpoint. Here we describe the evolution of the field of photo- and redox-driven artificial molecular motors, and we provide a comprehensive review of the work published in the past 5 years. After an analysis of the general principles that govern controlled and directed movement at the molecular scale, we describe the fundamental photochemical and redox processes that can enable its realization. The main classes of light- and redox-driven molecular motors are illustrated, with a particular focus on recent designs, and a thorough description of the functions performed by these kinds of devices according to literature reports is presented. Limitations, challenges, and future perspectives of the field are critically discussed.

CONTENTS 5. From Movements to Functions 237 5.1. Control of Chemical and Physical Properties 238 1. Introduction 201 fi 5.1.1. Transfer of Chirality 238 1.1. Terms and De nitions 201 5.1.2. Catalytic Properties 240 1.2. Directional Motion in Molecular Systems 202 5.1.3. Biological Functions 241 1.2.1. Energy Ratchet 202 5.2. Transmission of Directed Motion within 1.2.2. Information Ratchet 204 Molecular Systems 243 1.3. Energy Supply and Autonomous Behavior 205 5.3. Locomotion at the Nanoscale 246 1.3.1. Chemical Stimulation 205 5.3.1. Molecular Swimmers 246 1.3.2. Electrical Stimulation 207 5.3.2. Surface-Roving Nanovehicles 247 1.3.3. Optical Stimulation 207 5.4. Controlled Transport of Molecular Cargos 248 2. Redox-Driven Motors 209 5.4.1. Systems Based on Linear Molecular 2.1. General Considerations 209 Switches 248 2.2. Useful Redox Processes 210 5.4.2. Systems Based on Rotary Molecular 2.3. Supramolecular Pumps 210 Switches 249 2.4. Molecular Rotary Motors 213 5.5. Amplification of Motion by Collective Strat- 3. Photochemically Driven Motors 216 egies 250 3.1. General Considerations 216 5.5.1. Doped Liquid Crystals 251 3.2. Useful Photoinduced Processes 216 5.5.2. Self-Assembled Systems 252 3.3. Supramolecular Pumps 221 5.5.3. Systems with Covalently Linked Molec- 3.4. Molecular Walkers 222 ular Motor Units 254 3.5. Catenane Rotary Motors 224 6. Conclusions and Outlook 255 3.6. Molecular Rotary Motors 226 Author Information 257 3.6.1. Overcrowded Alkenes 226 Corresponding Authors 257 3.6.2. Hemithioindigos 232 ORCID 257 3.6.3. Imines 233 Notes 257 3.6.4. Other Systems 235 3.7. Photochemically Triggered Chemically Driv- en Motors 235 Special Issue: Molecular Motors 4. Motors with Combined Photo- and Redox Activation 237 Received: May 9, 2019 Published: August 15, 2019

© 2019 American Chemical Society 200 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Biographies 257 Nevertheless, the construction and operation of systems with Acknowledgments 257 a level of structural and functional sophistication close to that of References 257 natural molecular motors is still a prohibitive task. What chemists have been doing is making simple prototypes consisting of a few molecular components that can move relative to one another in a controllable way and tackling the 1. INTRODUCTION challenging problems posed by the interfacing of such devices Living organisms are equipped with a myriad of complex with the macroscopic world in terms of energy supply, molecular assemblies, called motor proteins, that work inside information exchange, and in more recent years, the task cells for ordinary needs like machines in a manufacturing performed. The many remarkable achievements in this area have − 24−41 plant.1 4 Scientific progress in the past decades has shown that been evidenced in several reviews (including some focused 42−46 47−54 these extremely small motors are in fact the most useful on redox-driven and light-driven systems), themed 55−58 59−61 62−65 machines for humankind, because they are tasked with executing issues, edited books, and monographs. The crucial processes for life. The most important and best known scientific value of molecular machines was highlighted by the motor proteins are those of the myosin5 and kinesin6 families, award of the 2016 Nobel Prize in Chemistry to Jean-Pierre ATP synthase,7 and the bacterial flagellar motor.8 Myosin and Sauvage,66 Fraser Stoddart,67 and Ben Feringa68 well before kinesin are linear motors powered by a chemical reaction these systems could impact significantly on people’s lives.69 namely, the hydrolysis of adenosine triphosphate (ATP)and Clearly, besides the relevance for fundamental science, the are responsible for, among other functions, contraction and Nobel Committee recognized the huge potential of molecular relaxation of muscles and transport of cargos around the cell, machines for major progress in several areas of technology and respectively. ATP synthase and the bacterial flagellum are rotary medicine, with ground-breaking applications limited only by motors, both driven by transmembrane proton gradients, whose imagination.70 functions are manufacturing of ATP in all organisms and This review will cover the progress achieved in the past 5 years locomotion in some classes of bacteria, respectively. Another in the area of molecular motors operated by redox and/or remarkable example is DNA polymerase, which moves along photochemical processes. Molecular motors are a subcategory of DNA while performing transcriptions.9,10 Several other key molecular machines (see section 1.1 for definitions). In order to biological processes, such as protein folding and unfolding,11 are provide a complete and meaningful representation of this rapidly − driven by molecular motors.1 4 Surely, these biomolecular growing area, studies prior to 2014 that are particularly mechanical devices provide a compelling demonstration of the significant for historical, tutorial, or scientific reasons or are feasibility and utility of nanotechnology and constitute a sound still the sole examples of a given type of device will also be scientific basis for attempting the construction of wholly artificial included. We will focus on systems in which the motor function machines that operate at the molecular scale. is inherent either to the individual molecule or, in the case of Although the latter idea was proposed for the first time by supramolecular complexes, to a minimal number of molecular Richard Feynman in his landmark 1959 talk,12 only in the past components. Therefore, materials and devices whose motorlike three decades has the progress in several areas of chemistry behavior is determined by the collective action of molecular primarily, the tremendous development of new synthetic, switches (which are not motors) and/or rectification features analytical, and computational tools to make and investigate arising from the anisotropy of the material or its environment complex molecular assembliesenabled its practical realization. will not be considered here. Interested readers can refer to recent − − In the 1980s, research in supramolecular chemistry triggered the articles71 82 and reviews83 91 on redox- and photoinduced creativity of the chemical community, and the possibility that the mechanical actuation and propulsion in nanostructured systems concepts of macroscopic device and machine, typical of and materials. engineering, could be transferred to the molecular level started 1.1. Terms and Definitions to arise.13,14 Specifically, it was proposed that molecules could be used as building blocks to construct nanoscale devices and As discussed in the previous section, the macroscopic concepts machines by a bottom-up approach.15 In the following years, as a of device and machine can be transferred to the molecular level. result of the rapid growth of supramolecular chemistry16 A molecular device is defined as an assembly of a discrete particularly in its broader meaning of the chemistry of number of molecular components designed to execute a 15,16 multicomponent speciesand mastering of the mechanical predetermined task. While each part performs a single act, bond between molecules,17,18 it became clear that the molecular the multicomponent (supramolecular) assembly can achieve a bottom-up approach offers virtually unlimited possibilities for more complex function that results from the cooperation of the the realization of nanoscale machines. Single-molecule micros- molecular components and is therefore inaccessible to them copies have provided direct observations of molecules as individually. A machine is a device characterized by the use of nanoscale objects endowed with size and shape that can move, mechanical power, i.e., controlled motion;92 analogously, a interact, and react. Indeed, the visualization by fluorescence molecular machine is a type of molecular device in which the microscopy of the rotation of a single molecular filament driven components can be set in motion relative to one another in a 19 by an F1-ATP synthase motor was not only a remarkable controlled manner, resulting in the potential ability to carry out a research achievement but also an exciting moment for function.36,38,62,63 nanoscientists. Finally, the physical concepts underlying the The comparison between macroscopic and molecular motion of very small objects20,21 and the operating principles of machines based on the iconic juxtaposition of movements biomolecular motors22 started to be elucidated in the chemical such as stretching, rotation, shuttling, braking, etc. has the community,23 leading to an increased mechanistic under- advantage of providing a simple representation of molecular standing of artificial molecular machines and providing rational machines (e.g., by cartoons that clearly show the mechanical guidelines for their design and interpretation of their behavior. function) and has greatly contributed to the popularization of

201 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review the topic and the growth of this new research area. As the field has evolved, however, it has became clear that such a comparison exposes one to the risk of overlooking the fundamental differences between the macroscopic and molecular realms. Indeed, nanoscale machines are not shrunk versions of the macroscopic ones, and their operating mechanisms cannot be devised on the basis of simple scaling rules.93 For example, the effects of gravity and inertia, which are so important for macroscopic motion, are fully negligible at the molecular scale, where viscous forces resulting from intermolecular interac- tionsincluding those with solvent moleculesdominate. Another fundamental issue is the fact that molecules are constantly moving because of their kinetic energy and that of their surrounding molecules as determined by the temperature. Such random thermal fluctuations, or Brownian motion, seem to preclude the controlled precision typical of machinelike operation. Motor proteins, however, demonstrate that appro- priately designed molecules can perform specific and directed movements when triggered by external stimuli. A crucial point for the present discussion is the definition of “molecular motor” and its relation to “molecular machine” and “molecular switch”. In line with recently proposed and generally accepted definitions36,38,63,65 evolved from earlier descrip- tions,24,25,62 a molecular motor can be considered as a type of molecular machine capable of performing work on its environ- ment in a progressive fashion. This result is achieved by using an energy source to repeat directionally controlled movements, which is the key challenge behind the construction of molecular Figure 1. In a rotary switch (a), the interconversion between two states motors. can take place by the same pathway traveled in opposite directions. The The peculiarity of a molecular motor can be better understood work done in the “forward” half-cycle (green arrows) is canceled in the “backward” one (red arrows). In a rotary motor (b), the forward and by comparison with the behavior of a molecular switch (Figure ff 1).94,95 The latter is a multistate system whose properties (and backward transitions between the two states follow di erent pathways, and net work can be performed. Transition states are represented with the consequent changes caused in the surroundings) are a pale colors. function of its state. The interconversion between two given states of a molecular switch can usually occur by the same pathway traveled in opposite directions (Figure 1a). In such a motion is disruptive: the thermal noise power experienced by a − case, any mechanical effect produced on the environment is molecule (∼10 8 W) is at least 8 orders of magnitude larger than canceled out when the switch returns to its original state (unless the power typically provided to a motor protein by the fuel the switch is coupled with another stimuli-controlled process reaction.21 Therefore, obtaining controlled and directed move- that desymmetrizes the switching cycle, in which case a ratchet is ment at the molecular scale is like walking in a hurricane or obtainedsee section 1.2). In particular switches, however, it during an earthquake: as the latter cannot be stopped, the only can happen that the “forward” transition between two states way to move forward is to exploit its random shakes.96 This is follows a route different from that of the “backward” transition. exactly what biomolecular motors do: they use an energy source A typical and simple example is that of a rotary device to bias Brownian motion such that the moves in a given direction undergoing 360° unidirectional rotation through two direction- are more likely than those in other directions. This result is ally correlated half-rotations (Figure 1a). This kind of switch can achieved by employing ratchet mechanisms, which operate by influence a system as a function of the switching trajectory, and a breaking spatial and time-reversal symmetries along the task performed in a full cycle is not inherently nullified. direction of motion with the application of a time-dependent 97 Hence, generally speaking, molecular motors are also switches potential with repeating asymmetric features. Ratchets of whose states differ from one another for the relative positioning interest in the present context can be divided in two categories: of some molecular components. To be a motor, however, a energy ratchets and information ratchets. Here we recall the switch needs to possess the additional feature of cycle basic aspects of these mechanisms with the help of examples directionality described above. Only molecular motors can use showing their chemical implementation. For consistency with an energy source to drive a molecular-scale system progressively the scope of this review, we describe systems activated by redox and repetitively away from chemical equilibrium. The vast and/or optical stimuli. A more thorough discussion and other majority of artificial molecular machines reported to date do not representative examples of ratchet mechanisms applied to − possess such an ability and are therefore mechanical switches but molecular machines can be found in refs 23, 31, 36, 38 40, − not motors. As pointed out in the previous section, in this review and 98 102. fl we will deal exclusively with molecular motors. 1.2.1. Energy Ratchet. In an energy ratchet, or ashing ratchet, the moving object is subjected to a potential energy 1.2. Directional Motion in Molecular Systems profile that is modulated periodically by means of an external Molecular-scale objects are subjected to the ceaseless random stimulus. The energy landscape consists minimally of two motion caused by thermal energy. At ambient temperature, this alternating maxima and minima that are repeated in space or

202 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review time (Figure 2). A Brownian particle is initially located in the modulation of the energy profile occurs independently of the absolute minimum; raising such a minimum and/or lowering the position of the particle. The concept of an energy ratchet has been nicely put into practice with mechanically interlocked molecules (MIMs) such as rotaxanes23,103 and catenanes.103,104 An interesting example based on redox and optical stimulation is the [2]rotaxane (E)- 14+ (Figure 3).105 Such a multicomponent species is based on a well-studied architecture106 comprising a cyclobis(paraquat-p- phenylene) (CBPQT) tetracationic macrocycle107 as a π- electron acceptor and an axle containing tetrathiafulvalene (TTF) and 1,5-dioxynaphthalene (DNP) units as π-electron donor ring recognition sites. In 14+, a photoactive 3,5,3′,5′- tetramethylazobenzene moiety (AB), which can be reversibly and efficiently switched between its E and Z configurations by light irradiation, is located between the TTF and DNP units. Since the TTF unit is more π-electron rich than the DNP one, the electron-poor CBPQT ring preferentially encircles the TTF unit rather than the DNP one in the starting co-conformation (Figure 4). Upon chemical or electrochemical oxidation of the TTF site to its radical cation, the potential energy well determined by the donor−acceptor interaction with the CBPQT ring is canceled, and a driving force for the motion of the ring toward the DNP unit is created. If the AB unit is in its E configuration, such a ring shuttling occurs at a high rate (Figure 4). Reduction of the previously oxidized TTF unit produces a driving force for the return of the macrocycle to the original position. The results showed that on the experimental time scale, this process is immediate if the AB unit is in the E configuration but does not occur at all if the AB unit has been photochemically isomerized to the Z form prior to the TTF reduction (Figure 4). This behavior can be explained by considering that the E → Z isomerization of azobenzene affords a large geometrical change capable of substantially affecting the energy barrier for the shuttling of the macrocycle along the axle component. Indeed, the Z-AB unit poses a much larger steric hindrance to ring Figure 2. Operation of an energy ratchet (or flashing ratchet). shuttling than does the E isomer, and the CBPQT ring is trapped Repeatedly changing the relative depths of the energy wells and the in a nonequilibrium state (Figure 4b). At the end, a Brownian relative heights of the energy barriers, as shown by the open arrows in particle (the macrocycle) has been transported energetically (a) and (b), causes a particle (black circle) to be moved directionally by uphill as a result of the redox-induced modulation of the energy exploitation of its Brownian motion. wells and the photoinduced modulation of the energy barrier. In this particular system, the correct sequence of changes in adjacent minimum such that the wells are inverted in depth will the minima and maxima necessary for the flashing ratchet is generate a driving force for the particle to move to the new ensured by the orthogonality of the processes triggered by the absolute minimum by thermal motion. To achieve direction- redox and optical stimuli. An intrinsically synchronized ality, also the relative heights of the two maxima need to be modulation can be achieved by using a single stimulus that modulated in order to make the forward motion faster (i.e., more triggers simultaneous changes in the wells and barriers (see, e.g., likely) than the backward one. The changes in the depth of the sections 2.3 and 3.3). It is important to note that a rotaxane- minima and the height of the maxima are produced by (an) based energy ratchet such as 14+ is able to produce a external signal(s) and have to be repeated to afford progressive nonequilibrium distribution of rings between the two stations and directed transport of the Brownian object. Notably, the and that while such a distribution is being reached the system

Figure 3. Structural formula of the photo- and redox-responsive rotaxane (E)-14+.105

203 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 4. Schematic representation of the redox and photochemically triggered switching processes in rotaxane 14+.105 (a) Initially the CBPQT ring encircles the TTF site on account of stronger π-electron donor−acceptor interactions than with the DNP site. Oxidation of the TTF site while the azobenzene unit (AB) is in the E configuration (process 1) is followed by the fast translation of the ring to the DNP site by Brownian motion. Irradiation of the oxidized rotaxane at 365 nm causes the isomerization of the azobenzene unit to the bulkier Z configuration (process 2) without affecting the position of the ring along the axle. Upon regeneration of the TTF primary station by reduction (process 3), a driving force for the return of CBPQT on the TTF site is created; however, because of the presence of the Z-AB stopper, the ring remains blocked in a nonequilibrium state. Therefore, as shown by the simplified potential energy curves (b), the macrocycle has been moved energetically uphill by an energy ratchet mechanism. could in principle do work. When a steady state is obtained, by Brownian motion; directional control is achieved by however, no more rings are transported (i.e., no more work can selectively decreasing the barrier “in front” of the particle be performed), and reset may occur only by a reciprocal path (in relative to the desired direction of motion (Figure 5)or the case of 14+, this is enabled by thermal or photochemical Z → selectively increasing the barrier “behind” the particle. It should E isomerization). Hence, this kind of device cannot be be noted that the relative depths of the energy minima are considered a molecular motor. Despite this limitation, unchanged. An information ratchet, as the name suggests, rotaxane-based ratchets have proved useful to gain a better implies the transfer of information from the particle to the understanding of rectification of Brownian motion and its energy profile. This cannot happen for free, or the second law of realization with synthetic molecules. Furthermore, the “un- thermodynamics would be violated: the information transfer productive steady state” problem can be circumvented by (i) process must be powered by an energy stimulus. dethreading the ring from a different extremity of the axle with The first example of a molecular information ratchet is the respect to that where it was threaded (see the pseudorotaxanes rotaxane 22+ shown in Figure 6.108 The system consists of a in sections 2.3 and 3.3) or (ii) linking together the two dibenzo[24]crown-8 (DB24C8)-based macrocycle surrounding extremities of the axle, devoid of the stoppers, to obtain a an axle endowed with two recognition sites for the ring, namely, [2]catenane (see section 3.5). The infinite periodicity of the a dibenzylammonium (DBA) unit and a monobenzylammo- potential energy profile that is necessary for the continuous nium (MBA) unit. These sites bind the ring by hydrogen directed motion of the Brownian particle is restored in space in bonding with comparable affinities but are distinguishable for the pseudorotaxane and in time in the catenane. In both cases, the purpose of monitoring the system. A methylstilbene unit directed motion can continue even when the applied stimulus (MS) asymmetrically divides the axle into two compartments, produces a stationary distribution of the components, and a each containing an ammonium site. When the MS unit is in the E molecular motor is obtained. form, the ring can travel randomly along the full length of the 1.2.2. Information Ratchet. In an information ratchet, the axle; conversely, when the MS unit is in the Z form, the ring is energy profile is modified as a function of the position of the trapped in one of the two compartments. Therefore, similar to particle along its path. As in the previous case, the object moves the azobenzene moiety in the previous example, the stilbene unit

204 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

closed) when the ring is in the MBA compartmentthat is, held far from the gate (Figure 6c). The system starts with the gate open (E-MS) and an equilibrium ring distribution of 65(DBA):35(MBA). Light irradiation in the presence of a suitable amount of benzil brings the system to a photostationary state in which the ring distribution becomes 45(DBA):55(MBA). In other words, about one-third of the macrocycles that occupied the more energetically favorable DBA site at equilibrium have been moved to the less favorable MBA compartment. Ultimately, the difference in the photoreactivities of the various interconverting isomers of 22+ (Figure 6) leads to a ring distribution between the two sites under light irradiation that is different from that observed at equilibrium in the dark. It should be pointed out that in this system photons are not used to modify the binding energy between the ring and either station but rather to power an information transfer process, as schematically indicated in Figure 5. In fact, driving the ring distribution away from its equilibrium value is ensured only by the fact that the macrocycle “signals” its position to the gate, which opens (or closes) accordingly. The similarity of these processes with the hypothetical task performed without an energy input by Maxwell’s demon in the famous thought experiment has been extensively discussed.31,36,109 However, rotaxane 22+ and other similar molecular information ratch- ets99,104 do not threaten the second law because of the required Figure 5. Operation of an information ratchet. A Brownian particle energy input. For the reasons discussed in the previous section, (black circle) can move directionally by selective lowering of the barrier 22+ is not a molecular motor because directed transport steps in front of it along the direction of motion. This requires transfer of cannot be repeated in a short rotaxane structure. A way to obtain information from the particle to the landscape, which can be achieved, an infinitely periodic energy profile with a small molecule is to for example, if the particle signals its position by interacting with the resort to a catenane structure.104 landscape in a distance-dependent manner, as schematically depicted in (a) and (d). 1.3. Energy Supply and Autonomous Behavior As pointed out earlier, movement is an intrinsic (and unavoidable) property of molecular systems. Because of the plays the role of a photocontrolled gate for the motion of the second law of thermodynamics, however, molecular machines macrocycle between the two recognition sites. With the stilbene cannot be driven by thermal energy at a constant temperature: to unit in the E formthat is, with the gate openthe system is at perform a task they have to be fueled by an energy source. This thermal equilibrium, and the distribution of the ring between the feature is shared with macroscopic machines. A common two sites, namely, 65(DBA):35(MBA), reflects their relative operation mode of the latter relies on temperature differences affinities for the ring (Figure 6a). To drive the ring distribution obtained by burning of a fuel, as happens in combustion engines. 12 away from equilibrium, the gate should be closed most of the As pointed out by Feynman, such a mechanism is impossible time and opened preferentially when the macrocycle occupies a for molecular machines because of the very fast heat dissipation specific position (in this case the DBA station). The first over nanometer distances. Nevertheless, the vast majority of requirement is obtained by adding to the solution a suitable biomolecular motors are powered by an exergonic chemical photosensitizer (benzil), which leads to a photostationary state reactionnamely, ATP hydrolysisthat happens at constant rich in the Z form of MS by intermolecular triplet sensitization. temperature. In these systems, motion arises from a complex The second requirement is accomplished by appending to the mechanochemical cycle that couples binding/unbinding events with the fuel reaction in such a way that the energy of ATP ring another photosensitizer (benzophenone) that is capable of − causing the E−Z photoisomerization of the stilbene gate by hydrolysis is eventually converted into mechanical work.1 6 intramolecular triplet sensitization. Benzophenone was chosen The way in which energy is administered to an artificial because it leads to a photostationary state richer in the E isomer molecular motor is a crucial issue that has to be carefully of MS compared with benzil. A key feature of the system is that considered from the initial design stages to the experimental the DBA station is very close to the stilbene gate, whereas the validation of the motor operation. Three fundamental MBA station is far from it. Therefore, it can be expected that approaches can be employed to supply energy to chemical intramolecular (benzophenone) sensitization (i.e., gate open- systems and thus to power molecular machines and motors. ing) is more efficient when the macrocycle is in the DBA 1.3.1. Chemical Stimulation. The most straightforward compartment, whereas the efficiency of intermolecular (benzil) way to feed energy into a chemical system is by adding a reactant sensitization should be independent of the position of the (“fuel”) that undergoes an exoergonic reaction, as happens in macrocycle. Conditions are chosen so that the benzophenone- biomolecular motors. Ideally, the fuel has to be delivered where sensitized isomerization dominates (gate open) when the ring is and when needed. Its reaction will necessarily generate products in the DBA compartmentthat is, held near the gate (Figure (“waste”) that, even in the favorable case where they do not 6b)whereas the benzil-sensitized reaction dominates (gate interfere with the operation of the machine, will accumulate in

205 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 6. Molecular information ratchet based on the photoisomerizable bistable rotaxane 22+.108 Dashed arrows indicate processes that are unlikely to occur.

Figure 7. (a) Schematics of a molecular system that exploits two different reactants (a fuel and an antifuel) to switch between two structurally different equilibrium states. Repeated switching (cycling) requires the sequential addition of fuel and antifuel. (b) An autonomous chemically driven molecular machine that exploits the catalytic decomposition of a fuel to perform the transformation between two structurally different states. The process can continue indefinitely without the intervention of an operator as long as the fuel is available. In both cases, waste products are formed. the reaction medium unless they are appropriately removed. It is reset the switching process and close the cycle (Figure 7a). Such worth noting that the waste of ATP-driven motor proteins behavior, which requires alternating additions of fuel and namely, ADP and inorganic phosphateis not only removed antifuel (simultaneous addition of the fuel and antifuel would but also recycled into new fuel by ATP synthase, providing a normally lead to a fast reaction between them, thereby nullifying magnificent example of circular economy at the molecular scale. their function), results in an “operator-dependent” working An important quality of chemically driven molecular cycle. In other words, the machine is not capable of using the machines is the way in which they exploit the fuel. If the chemical energy input in an autonomous fashion. This is the most reaction of the fuel leads the system into a new equilibrium state, common situation for artificial molecular machines and motors as happens in thermodynamically controlled molecular switches, developed to date, in which the fuel/antifuel are typically another reactant (the “antifuel”) must be added in sequence to oxidant/reductant or acid/base reactants.

206 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

In contrast, biomolecular motors can autonomously repeat fascinating from a fundamental viewpoint but also potentially their operating cycle without external intervention as long as the useful for nanofluidics and the development of ferroelectric fuel is available. This is the case because such systems exploit the materials. Although several molecular dynamics simulations fuel in a catalytic manner; that is, they act as catalysts for the studies are available, in only a few cases have the molecules been decomposition of the fuel (Figure 7b). While performing the synthesized and investigated under the influence of an electric catalytic cycle during which the fuel is transformed, the field.121,122 These devices will not be described in detail here molecular motor travels along different mechanical states, because redox processes are not at the basis of their functioning. ultimately exhibiting controlled motion. As a matter of fact, 1.3.3. Optical Stimulation. Although sunlight is the sole myosin and kinesin are catalysts for the hydrolysis of ATP that energy input on which our planet can rely, the direct conversion are able to use the resulting energy to bias Brownian motion. of solar radiationor, more generally, light energyinto Only one case of an autonomous fuel-driven synthetic molecular mechanical movements is a rare event in nature. At the 104 motor has been described to date, and examples based on molecular level, a remarkable example of photoinduced motion redox processes have not yet been reported. to perform functions is provided by retinal, the chromophore A key feature of the catalytic operation mode is that the involved in vision and in bacteriorhodopsin proton pumps.123 In ff di erent mechanical states of the motor are not equilibrium biological systems, light energy is converted through photo- states for the whole system (motor and fuel). The system synthetic processes to produce chemical fuels for the very same operates away from thermodynamic equilibrium, which is reasons related to the exploitation of solar energy in technology: eventually reached when the fuel is gone. It is worthwhile to sunlight power is diffuse and intermittent, and it has to be recall, however, that out-of-equilibrium conditions can also be converted to other forms to be accumulated or trans- obtained with carefully designed molecular machines that ported.124,125 On the contrary, chemical fuels such as the ATP consume a fuel and an antifuel in a nonautonomous fashion suitable for powering biomolecular motors can be stored and (see, e.g., section 2.3). Therefore, the ability to autonomously delivered on command. exploit an energy source is a desirable but not essential Nevertheless, light energy can cause reactions that involve requirement for a molecular motor. large structural changes in molecular systems, thus transforming 1.3.2. Electrical Stimulation. Macroscopic motors pow- fi optical stimuli into motion. Several classes of photochemical ered by electrical energy are widely used in all elds of reactions of organic and inorganic species, such as isomerization, technology. One may wonder whether it is possible to use dimerization, addition, rearrangement and decomposition, may − electrical energy to power molecular motors too. If one be considered for this purpose.126 128 It is also well-known that considers molecular motors operating via chemical reactions, electronically excited states generated by the absorption of light the answer is yes, because it is well-known that redox reactions possess significantly different redox and acid−base properties promoted by the application of electrical potentials can cause − with respect to the ground state, thus allowing photoinduced structural changes in (supra)molecular systems.42 46,110,111 If a electron- and proton-transfer processes, which can also cause reversible redox couple is utilized, after the forward reaction is major displacements of the molecular parts in multicomponent triggered, the return to the starting species is made possible by systems. For a more detailed description of these phenomena, changing the applied potential, and a switching process can be see section 3.2. carried out without the formation of waste (although waste fi products may be formed at the counter electrode, they can be The use of optical stimuli to power arti cial molecular kept separated from the operating environment of the machine). machines has several advantages with respect to chemical fuels. Electrical potentials, unlike the addition of chemical oxidants First of all, by relying on clean and reversible photochemical and reductants, are readily turned on and off and can be applied reactions, it is possible to design machines powered solely by locally with high resolution by means of ultramicroelectrodes light that do not generate waste. Modulation of the wavelength and related probe microscopy techniques.112 Electrochemistry and intensity of light in relation to the absorption spectrum of offers powerful analytical tools (e.g., the various kinds of the targeted species enables careful control of the amount of energy supplied to the system. Such energy can be transferred to voltammetry) to characterize molecular-scale systems from both “ ” the thermodynamic and kinetic points of view as well as the molecule without any physical connection, or wiring ,to convenient ways to interface them with the macroscopic world the source; the only requirement for remote excitation is the through modification of the electrodes. In summary, by transparency of the matrix at the irradiation wavelength. Light exploiting electrochemically induced processes, one can may also be delivered to particular places (e.g., inside an fi “write” (i.e., cause changes) and “read” (i.e., monitor) chemical instrument or in the human body) with the aid of optical bers. systems with control in time and space. Modern light sources such as lasers and light-emitting diodes Electrical energy can also be supplied to chemical systems enable investigations in very small spaces and extremely short without causing redox processes. For example, individual time domains, and excitation with nanometer resolution is molecules deposited on a conducting surface could be possible with near-field techniques. Conversely, parallel electronically and/or vibrationally excited by the application addressing of a very large number of individual molecular of an appropriate voltage with a local probe, such as the tip of a machines can be achieved upon irradiation of large areas and scanning tunneling microscope (STM). In recent years, this volumes. Another significant difference between chemically approach was followed to accomplish directed motion of single driven and light-driven molecular machines129 is that photo- molecules on surfaces,113 leading to outstanding examples of induced processes can directly result in motion and generation rotary motors114,115 and “nanocars”116,117 that can be engaged in of force, thus deterministically relating the energy input with the nanoscale races.118,119 Another possibility is to use externally “power stroke” of the machine. Last but not least, as already applied variable electric fields to drive the directional rotation of pointed out in the previous section for electrochemical inputs, surface-mounted molecular rotors comprising dipolar sub- the interaction between photons and molecules can both supply components.27,32,120 Systems of this kind are not only highly the energy necessary for the functioning of the machine and

207 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 8. Structural formula of the photochemically driven molecular shuttle 36+.135 provide information about its state by means of spectroscopic techniques.130,131 A further element of interest about optical stimulation is that the use of reversible photochemical processes in appropriately designed molecules can enable the development of motors that function autonomously, that is, repeat their operating cycle under constant experimental conditions as long as the light source is available. This result is achieved by devising a mechanism based on a photoinduced sequence of processes that lead the system through transient electronic and (co)- conformational (mechanical) states, with the final deactivation of the system to the ground state providing an automatic reset and closing the cycle.132 The successive absorption of another photon triggers a new cycle, and the process can be repeated indefinitely at a frequency that depends on the time scale of the transformations comprised in the operating cycle (unless irradiation is performed at such a low flux that the rate of incoming photons determines the reaction rate). These concepts are exemplified by the [2]rotaxane 36+ (Figure 8), a molecular machine designed to exploit the energy of visible light in an autonomous manner to repetitively shuttle a macrocycle back and forth along a track.133 The ring component of 36+ is a π-electron-rich crown ether, whereas the axle comprises several covalently linked units, namely, a Ru(II) Figure 9. (a) Schematic representation of the autonomous light-driven polypyridine complex, a p-terphenyl-type rigid spacer, π- shuttling of 36+.133 Processes 2 and 4 are in competition with undesired electron-poor 4,4′-bipyridinium (BPY) and 3,3′-dimethyl-4,4′- reactions, represented by dashed lines. The mechanism is based solely bipyridinium (DMB) units, and a tetraarylmethane group as the on intramolecular processes and no waste is produced. (b) Simplified potential energy profiles for each structure in (a) as a function of the terminal stopper. The ruthenium-based moiety plays the dual − role of a photosensitizer and a stopper, whereas the mechanical ring axle relative position. switch consists of the two electron-poor recognition sites and the electron-rich macrocycle. In the stable co-conformation of 5). Once the macrocycle has moved away from its starting the rotaxane, the ring encircles the BPY site because it is a more location, back electron-transfer from the reduced (and efficient electron acceptor than the DMB one. uncomplexed) BPY unit to the oxidized Ru-based unit (process The photoinduced shuttling of the macrocyclic ring between 6) regenerates the primary recognition site by restoring its the BPY and DMB sites is based on a four-step sequence of electron acceptor properties. As a consequence of such an electron transfer and molecular rearrangement processes “electronic reset”, the ring moves from DMB to BPY by (Figure 9a). Visible-light excitation of 36+ (process 1) generates Brownian motion (process 7).134 The cycle is thus completed, the lowest singlet excited state (1MLCT) of the Ru-based unit, and the rotaxane is ready to process another photon. Therefore, which quickly deactivates to the lower-lying triplet level the spontaneous thermally driven reset of the molecular (3MLCT). This triplet is relatively long lived (∼1 μsin machine enables its autonomous operation under the supply deoxygenated solution at room temperature), and the redox of light energy at a frequency of about 1 kHz at room potential for its oxidation is ca. −0.8 V versus the standard temperature. calomel electrode (V vs SCE). As the monoelectronic reduction As happens for macroscopic motors, the successful operation of BPY takes place at about −0.4 V vs SCE, the transfer of an of this nanomachine relies on a correct synchronization of the electron from the excited Ru-based moiety to the BPY site processes at the basis of the mechanism (Figure 9). Such a result (process 2) is thermodynamically downhill. This reaction is in implies fine control of the kinetics and can be achieved by careful competition with the inherent decay of the 3MLCT state structural design. Because of competition with undesirable (process 3). energy-wasting processes (primarily the back electron-transfer After the reduction of the BPY recognition site and its process; step 5 in Figure 9), the overall quantum yield for ring consequent deactivation, the macrocycle migrates by 1.3 nm to shuttling is only 2%. The molecular shuttle 36+ can also be encircle the DMB unit (process 4). This process competes with operated with a higher quantum yield by a sacrificial mechanism the back electron-transfer from the reduced BPY site, still involving irreversible reducing (triethanolamine, tea)and 135 surrounded by the ring, to the oxidized photosensitizer (process oxidizing (O2) species (Figure 10a) and by an intermolecular

208 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 10. Alternative mechanisms for the photochemically triggered ring shuttling in 36+: (a) nonautonomous operation involving two sacrificial fuels; (b) photon-only autonomous operation assisted by an electron relay. mechanism based on the kinetic assistance of a reversible motors.125 Nevertheless, electron transfer processes are of electron relay (phenothiazine, ptz; Figure 10b).133,136 The crucial importance in many biological processes, particularly in sacrificial mechanism, however, does not allow autonomous combination with proton transfer, for both energy transduction operation and leads to consumption of chemical fuels and and signal transmission. For example, in photosynthesis the concomitant formation of waste. On the other hand, the captured light energy is converted into chemical energy by − assistance by an electron relay affords autonomous behavior in means of electron transfer reactions.123 125 Furthermore, in which only photons are consumed, but the mechanism is no aerobic organisms the reduction of oxygen to water, catalyzed by longer based solely on intrarotaxane processes and becomes cytochrome c oxidase, generates an electrochemical potential concentration-dependent. 6+ across the mitochondrial (or bacterial) membrane that results in In summary, 3 is a remarkable example of how optical inputs proton pumping against a chemical gradient, ultimately driving can be processed by a suitably designed molecule to achieve the synthesis of ATP by the ATP synthase rotary motor. controlled motion. The result is a molecular machine (not a From an artificial standpoint, redox reactions are an appealing motor) that (i) consumes only visible photons, (ii) operates option to power molecular motors because of the wide choice of autonomously, (iii) follows a unimolecular mechanism, and (iv) molecular redox switches and their versatile application in does not produce waste. Alternatively, the ability of a molecular 42−46 multicomponent species. Redox processes in solution can machine to exploit light energy in an autonomous fashion can be accomplished by addition of chemical reactants, by exploiting arise from photoinduced switching between different forms of photoactivated electron transfer processes, or by heterogeneous the photochromic compounds. Examples of this kind will be described in section 3. electron transfer reactions achieved by applying appropriate In addition to the advantages discussed above, the use of light electrical potentials to conducting electrodes. The use of to power nanoscale devices and machines has a more profound oxidizing or reducing agents enables the controlled oxidation justification. It is clear to (almost) everyone that the energy or reduction of a bulk solution, but it brings about all the problem and climate change are the most critical issues that limitations related to the addition of chemical reagents (see humankind has to face in the coming years, and it is clear that the section 1.3.1). Redox processes induced by light involve the products of a future nanotechnology-based industry will have to transfer of an electron from (or to) an excited photosensitizer to be powered by renewable and clean energy sources. In this (or from) the redox-active unit. The photosensitizer can be context, the construction of molecular motorsincluding either integrated within the molecular components or added in biomimetic137 and artificial−natural hybrids138,139that can solution to give a bimolecular reaction (see section 1.3.3). harness solar energy in the form of visible or near-UV light is Molecular motors powered by photoinduced redox reactions certainly an interesting possibility. will be described in section 3. The advantages of using an electrochemical setup to trigger 2. REDOX-DRIVEN MOTORS redox processes in the context of molecular machines have been discussed in section 1.3.2. It is worth recalling that electrical 2.1. General Considerations stimulation is also useful to afford redox processes in gels and As discussed in the previous sections, nature does not use redox solid materials, which can lead to mechanical actuation.86,89,90 In reactions to directly power movement in biomolecular general, the use of electrical energy to power mechanical

209 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review nanoscale systems is very promising for prospective techno- More recently, another class of redox reactions has proven logical applications. useful for the design of artificial molecular machines, i.e., the 2.2. Useful Redox Processes supramolecular association of chemically or electrochemically generated radicals in solution. The prototypical example of this The majority of redox-driven molecular machines and 42−46 kind of reaction is the dimerization of bipyridinium-based motors are based on catenane and rotaxane interlocked radical cations, obtained by reduction of the corresponding fi structures and rely on two general design approaches. The rst dications, in aqueous media.173 Such a process, also called one is based on redox control of the coordination geometry 25,26,32,66,140 pimerization, can be favored in the presence of a neutral host, around transition metal ions. Indeed, several such as a cucurbituril174 or cyclodextrin,175 whose cavity can ff transition metals can exist in di erent oxidation states and encapsulate the dimer. The pimerization of bipyridinium radical form a large variety of coordination complexes, whose nature cations has been exploited as an alternative recognition motif for (stoichiometry, geometry, ligand types) strongly depend on the new switchable host−guest complexes.176 As a matter of fact, a oxidation state. Thus, a rearrangement of the coordination two-electron-reduced CBPQT macrocycle (containing two sphere can be induced by modifying the oxidation state of the bipyridinium radical cations) and a monoreduced bipyridi- metal ion with a redox stimulus. This strategy was originally nium-based axle can self-assemble,177 forming strong host− developed by Sauvage and co-workers with a copper-containing − 141 guest complexes stabilized by radical radical interactions. This [2]catenane. One ring of the catenane contains a bidentate strategy has been harnessed for the construction of (pseudo)- phenanthroline ligand, whereas the second macrocycle has two rotaxanes,176,178,179 two- and three-station rotaxanes,176 and − chelating sites, namely, a phenanthroline and a tridentate catenanes.180 183 terpyridine ligand. As Cu(I) adopts a tetrahedral coordination It is worth noting that in a supramolecular context, a redox geometry, in the Cu(I) catenane the rings are arranged in such a reaction can be used to affect the minima and/or the maxima of way that the metal ion is surrounded by the two phenanthroline the potential energy surface that determines the mutual ligands. On the other hand, Cu(II) prefers to be pentacoordi- arrangement of the molecular components. As an example, the nated, and therefore, upon oxidation of the Cu(I) to Cu(II), the pimerization reaction of bipyridinium units can be considered: catenane undergoes a rearrangement that enables coordination upon reduction a stabilizing interaction is established between of the metal ion to one phenanthroline and one terpyridine the radical cations, which means that an energy well is formed. ligand. The initial situation is restored upon successive reduction On the other hand, reoxidation of the radicals to the doubly of Cu(II) to Cu(I). 142 charged species installs an electrostatic repulsion, and the energy This strategy has also been successfully implemented with well is converted into a barrier. The possibility to tune the rotaxane-based systems, in which different polypyridine ligands 143−148 electrostatic interactions for modulation of the potential energy are incorporated in either the axle or the ring component. surface associated with the motion is particularly valuable when Interestingly, the metal ion plays the dual role of a templating designing molecular motors that need to rely on energy ratchet element that enables the synthesis of the interlocked structure mechanisms (see section 1.2.1). and a redox-switchable unit that drives the mechanical motion. Another process triggered by redox reactions that can be Demetalation of the MIM and successive remetalation with a useful for molecular machines is the geometrical isomerization ff ff di erent ion (or the same ion in a di erent oxidation state) was of double bonds such as CC (e.g., in stilbene deriva- also employed to bring about molecular rearrange- 184−186  145,149,150 tives), C N (e.g., in imine and hydrazone deriva- ments. tives),187,188 and NN (e.g., in azobenzene derivatives).189,190 The second approach to the design of redox-controlled Oxidation or reduction of the molecule can lower the rotation mechanical devices is based on modulation of the electron barrier around a double bond by increasing its single-bond donor−acceptor interactions that occur between the molecular 151−155 character; moreover, catalytic mechanisms involving radical components of the interlocked structure. This strategy species can be activated, leading to fast isomerization. Hence, was originally developed by Stoddart, Kaifer, and co-workers156 107 molecular machines operated by photoinduced isomerization of with a rotaxane comprising a CBPQT cyclophane and an axle CC, CN, and NN double bonds (see section 3.2) could π containing two -electron-donor units, namely, biphenol and also be controlled, in principle, by redox stimulation. benzidine. This rotaxane exists as two translational isomers, It should be noted that although many examples of redox- wherein the macrocycle resides either on the benzidine station driven molecular machines have been reported in the − (84% occupancy) or the biphenol station (16% occupancy). literature,42 46 only a few of them can be considered as Upon oxidation of the former unit, electrostatic repulsion is molecular motors (see section 1). established between the positively charged macrocycle and the oxidized benzidine, and the CBPQT ring moves to encircle the 2.3. Supramolecular Pumps biphenol station exclusively. Since this seminal work, a large Molecular pumps are linear motors in which a molecular variety of donor−acceptor pairs have been exploited in the substrate is directionally transported with respect to the motor design and construction of redox-switchable molecular component. The transport must be active, that is, intrinsically − machines.42 46,157 Actually, a vastly exploited donor−acceptor performed by the motor using its energy source, without relying combination is the one involving 4,4′-bipyridinium moi- on external concentration differences; in principle, it should take eties107,158 as electron acceptors and tetrathiafulvalene (TTF) place against a concentration gradient. In this regard, molecular − derivatives159 163 as electron donors (see, e.g., compound 14+ in pumps are energy transducers capable of converting the energy Figure 3). This recognition motif, characterized by a clean and input of the device into a chemical potential; in other words, reversible dual switching mode (i.e., TTF oxidation or they can use an external energy source to generate a bipyridinium reduction),164 has been included in several nonequilibrium state.191 This behavior is opposed to that of − − supramolecular complexes165 167 and MIMs105,168 170 with passive transporters, which simply facilitate the system to relax potential for applications.171,172 to equilibrium: the cargo moves down a concentration gradient,

210 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review eventually exhausting it. It should be recalled that the controlled Therefore, chemical energy can in principle be stored in the transport of molecular and ionic substrates across biological system, even in homogeneous solution. membranes that define and separate compartments is a It should also be pointed out that the development of a − fundamental task for living organisms.1 4,191 The construction pseudorotaxane motif capable of performing unidirectional of artificial molecular devices capable of performing such a threading and dethreading processes under the control of function is motivated by the high basic science value and the external stimuli (Figure 11a) would be useful for the potentialfortechnologicalandmedicalapplicationsand construction of processive linear motors based on rotaxanes constitutes a flourishing area of research in supramolecular (Figure 11b) and rotary motors based on catenanes (Figure 37,192−195 chemistry. 11c). In recent years, artificial molecular pumps have been realized The problem of obtaining directionally controlled threading− by following supramolecular design approaches based on dethreading movements in pseudorotaxanes with appropriately fi (pseudo)rotaxane architectures. If the axle is de ned as the designed nonsymmetric components has been discussed by “ ” 198−204 track of the motor, then in these systems the ring component several research groups. Arduini, Credi, Venturi, and co- may be directionally moved (i.e., transported) along the track. It workers succeeded in directionally threading an oriented is worth noting, however, that in homogeneous solution, bipyridinium-containing axle into a calix[6]arene macrocycle wherein none of the molecular components is connected to a and preventing back-dethreading by stoppering one end of the fi xed reference system, only relative movements can be axle.101 The electrochemical reduction of the bipyridinium unit considered, and the distinction between the “transporting” “ ” did not cause dethreading, which was obtained, however, by and transported components is purely conventional. Two changing the solvent. Although the challenge of realizing a different classes of pumps have been described, depending on 196 stimuli-responsive molecular pump was met, the rather thenatureofthesystem. On the one hand, in a unpractical switching conditions and the need to perform a pseudorotaxane complex, the ring and axle molecules may selective destoppering reaction to reset the device limited the undergo unidirectional threading and dethreading. It can be interest of this approach. envisaged that the ring becomes associated with the axle by The first example of a redox-driven molecular pump was passing over a specific extremity of the latter; successively, the 205 reported by Stoddart and co-workers in 2013. It is based on a ring dissociates by exiting from the opposite side (Figure 11a). pseudorotaxane consisting of a CBPQT macrocycle (44+) and a nonsymmetric axle 5+ that comprises a 1,5-dioxynapthalene (DNP) recognition site in the center and a neutral 2- isopropylphenyl (IPP) group and a positively charged 3,5- dimethylpyridinium (PY) unit at the two extremities (Figure 12a). The operating principle of the system is schematized in Figure 12b: 44+ encircles the axle on account of charge-transfer interactions with DNP (energy minimum). There are two possible paths for threading, but they are characterized by different energetic barriers. In fact, the Coulombic repulsion between 44+ and the charged PY unit is stronger than the steric interaction with the neutral IPP group.206 Therefore, the passage of the ring is faster on the neutral group, and unidirectional threading is obtained. Upon reduction of the macrocycle, two effects are attained: (i) decreased stability of the complex (because the energy minimum is raised) and (ii) decreased Coulombic repulsion (with a drop of the energy barrier). Thus, Figure 11. (a) Schematic representation of the relative unidirectional ff transit of a macrocycle along a nonsymmetric molecular axle. By an energy ratchet mechanism is e ected (section 1.2.1): in the incorporating the system shown in (a) into a rotaxane (b) or a catenane destabilized complex, the relative heights of the two kinetic (c), linear or rotary motors may be obtained, respectively. barriers are reversed, and the reduced macrocycle passes over the PY end to dissociate, completing the unidirectional transit. On the other hand, semirotaxane architectures have been The redox processes were carried out by adding chemical reported in which a molecular ring passes over the unstoppered reagents (Zn powder and oxygen as the reductant and oxidant, end of the axle, travels directionally along it, and is eventually respectively), by performing an electrochemical reaction on a blocked in the stopper-terminated portion of the axle. In both conducting electrode, and by exploiting photoinduced electron classes the pumping cycle can be repeated, resulting in the transfer from a ruthenium polypyridine complex used as a passage of successive rings along the axle in the pseudorotaxane photosensitizer (section 3.3). Indeed, these results prove not species or the accumulation of more than one ring on the axle in only the solidity and flexibility of the reported system but also the semirotaxane species. In the former case, the threading− the general versatility of redox-controlled molecular devices. As dethreading cycle can produce a net effect only if the transport pointed out above, this pump does not perform work because involves spatially separated “departure” and “arrival” compart- the ring is taken up from and released into the same solution. ments. This result could be achieved, for example, by a The operating cycle can be repeated, but the outcomes of membrane that provides the boundary of the compartments successive cycles cannot sum up and lead to the buildup of an and the fixed support for the “transporting” component of the effect. Nevertheless, a system of this kind may prove useful for pump.197 Conversely, in the semirotaxane case the macro- the realization of processive linear motors based on polymers or cycle(s) can be pumped energetically uphill along the axle, for “energy reservoir” rotaxanes. The latter systems consist of which thus acts as a “reservoir” of ring(s) in a metastable state. rotaxanes wherein the macrocycle is forced to surround a

211 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 12. (a) Structural formulas of the molecular components 44+ and 5+ of a redox-driven molecular pump. (b) Schematized operation mechanism of the molecular pump and (c) simplified potential energy surfaces. Unidirectional threading is accomplished by exploiting the electrostatic repulsion between CBPQT and PY; upon electrochemical reduction, the potential energy minimum increases and the potential energy maximum for the passage of CBPQT over PY decreases, thus forcing the macrocycle to dethread unidirectionally. Adapted from ref 205. Copyright 2013 American Chemical Society. portion of the axle for which it has low or null affinity, forming a oligomethylene chain, a 4,4′-bipyridinium unit (BPY) as a metastable state.23,99,108 recognition site for the macrocycle, a longer chain, and a bulky 207 The first attempt to realize a redox-driven version of such 2,6-diisopropylphenyl (DIP) stopper at the opposite end. energetically demanding MIMs was based on a CBPQT ring The operating principle, depicted in Figure 14, relies on (44+ in Figure 12a) and a series of axle molecules 6a−i3+ (Figure modulation of the energy minima and maxima of the potential energy surfaces by tuning (i) the radical−radical interaction 13) comprising in sequence a PY unit at one end, a short between the monoreduced bipyridinium moieties of CBPQT and BPY and (ii) the Coulombic repulsion between the oxidized macrocycle 44+ and the PY end unit. Upon electrochemical reduction, both the energy barrier for slipping through PY and the energy minimum are decreased, thus promoting the ring− axle association. Upon successive reoxidation, electrostatic repulsions are reinstalled, and both the barrier and the well increase again. The ring is forced to move away from BPY; as it cannot slip over PY, it has no choice but to reside on the oligomethylene chain. It was found that the half-life of this metastable state depends on the lengths of the spacers connecting the central BPY unit to the two different extremities. Interestingly, a longer chain on the side of the stopper stabilizes the complex by keeping BPY and CBPQT far apart, whereas a shorter chain on the PY side increases the Coulombic repulsion, thereby enhancing the chemical inactivity of the nonequilibrium state. fi Figure 13. Structural formulas and cartoon representation of the axle Although these arti cial supramolecular pumps can dissipate components 6a−i3+ of a rotaxane that can pump one CBPQT redox chemical energy to transport a molecular species to a high- macrocycle (44+) energetically uphill. Adapted from ref 207. Copyright energy state, their design did not allow the collection of more 2014 American Chemical Society. rings in the axle by repeating the operating cycle. Nevertheless,

212 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

charged BPY and PY units destabilizes the complex and establishes an insurmountable kinetic barrier; consequently, the macrocycle overcomes the steric barrier exerted by IPP and moves toward the OME chain. In the second cycle of operation, a second ring is captured from the solution and transported into the collecting portion of the axle. Upon reduction, a competition for the monoreduced BPY site between a free and a complexed reduced CBPQT macrocycle is established. The IPP steric speed bump, however, provides a barrier for the return of the first entrapped ring onto the reduced BPY site, and threading of a second ring from the solution is kinetically favored. After reoxidation, the interaction is weakened and the electrostatic repulsion pushes the second ring onto the OME chain. Analysis of the kinetic and thermodynamic data for the systems suggested that the two ensnared CBPQT rings do not interact appreciably with one another; nevertheless, the number of cycles that can actually be performed depends on the length of the chain that collects the rings. Overall, this molecular pump can in principle operate repetitively, driving the system progressively further and further away from equilibrium. Repetitive operation was demonstrated on an oligomeric dual pump210 comprising two such modules209 connected by a quaternary-ammonium-based carbon chain. By alternation of two constant potentials at −0.7 and +1.4 V, respectively, up to four CBPQT macrocycles could be loaded on the axle, thus forming a [5]rotaxane. 2.4. Molecular Rotary Motors Figure 14. (a) Schematized mechanism and (b) potential energy curves Two different architectures have been exploited for the 4+ − 3+ for the pumping of macrocycle 4 along axles 6a i shown in Figure realization of artificial rotary motors: interlocked structures 13. Adapted from ref 207. Copyright 2014 American Chemical Society. based on catenanes103,104,211,212 and molecular motors based on rotation around a covalent or coordination bond as the axis.213 building upon these promising results, a more effective system As a matter of fact, to date there are no examples of redox-driven was realized that is able to create a local concentration gradient molecular rotary motors based on catenanes, and only a few by repetitively accumulating macrocyclic molecules along a examples of rotation around single or double bonds triggered by portion of the axle.208,209 The axle molecule 73+ (Figure 15)is electrochemical reactions are available. derived from compounds 6a−i3+ (Figure 13)207 and is endowed Feringa and co-workers reported a series of molecular rotary with an IPP “steric speed bump”206 between BPY and the motors based on overcrowded alkenes whose working principle collecting oligomethylene (OME) chain. The redox pumping is based on four alternating strokes of light and heat (see section mechanism is summarized in Figure 16. The first cycle of 3.6.1).213 By analogy to dithienylethene-based photochromic operation is similar to that of the previous example: the compounds, which can also be switched by electrochemical threading of the molecular components is triggered by oxidation, the possibility to drive the rotary motor by redox electrochemical reduction of the axle and ring molecules, stimulation has been explored.214 The chosen structure, which which enables the passage of the reduced CBPQT ring over PY belongs to the second generation of light-driven molecular and the formation of radical−radical stabilizing interactions. rotary motors (see section 3.6.1),215 contains sulfur atoms in Upon reoxidation, the Coulombic repulsion between 44+ and the both halves of the molecule. This structure is related to

Figure 15. Structural formula and cartoon representation of the molecular axle 73+ that can collect more than one CBPQT macrocycle 44+ in its alkyl chain reservoir by redox pumping. Adapted with permission from ref 208. Copyright 2015 Springer Nature.

213 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 16. (a) Schematized mechanism and (b) potential energy curves for the pumping of macrocycle 44+ along axle 73+. Adapted with permission from ref 208. Copyright 2015 Springer Nature. bis(thiaxanthylidene)s, which can be doubly oxidized, with loss to the ortho substituents in the upper and lower halves of the of the double-bond character of the central CC bond, and can molecule, thus lowering the barrier for rotation, and (ii) a chiral subsequently undergo free rotation around the single bond. element on group A, which converts the two atropisomers into Indeed, upon oxidation of the molecular motor, an orthogonal two atrop-diastereomers with different energies. The structure conformation can be adopted; subsequent reduction restores of the molecular motor 8 is shown in Figure 18: A is a chiral the central double bond, possibly blocking the system in both sulfoxide, and B and C are a H and a Br atom, respectively; the stable and unstable conformations. Upon thermal helix bridging unit is palladium in two different oxidation states. The inversion of the unstable conformation, a complete cycle operation mechanism is schematized in Figure 18: Pd(II) reacts would be accomplished. As a matter of fact, other redox-driven with the C−H ortho substituent of (S,M)-8 to form the bridged reactions prevent a full characterization of the system and its ffi complex Pd[(R,P)-9]XL, which is in equilibrium with the more e cient operation; nevertheless, this study suggests a possible stable Pd[(R,M)-9]XL isomer (X and L are anionic and neutral way to design redox-driven rotary motors. ligands, respectively). Subsequent transformation of the C−Pd Single bonds can intrinsically perform rotary motions, but in − 8 ° order make a motor, the random relative movements of the bond into a C H bond provides (S,P)- , completing a 180 molecular components must be directionally biased by the clockwise rotation. Treatment of (S,P)-8 with a source of Pd(0) 216 leads to the formation of the bridged complex Pd[(R,P)-10]BrL intervention of an external input. The design of such motors − is based on a biaryl with three ortho substituents: A on the after an oxidative addition reaction on the C Br bond. Again, “lower” aryl unit and B and C on the “upper” aryl unit (Figure the barrier to atropisomerization from Pd[(R,P)-10]BrL to 17). Full rotation around the central axis is prevented by steric Pd[(R,M)-10]BrL is lowered, and the equilibrium is shifted hindrance, and the molecule exists as two atropisomers (stations toward the latter compound. Reintroduction of the C−Br bond I and III in Figure 17). In order to obtain a rotary motor, the two on Pd[(R,M)-10]BrL completes the 180° clockwise rotation, aryl units must be able to perform a complete and unidirectional forming the starting compound (S,M)-8. It must be noted that in rotation. Two control elements are inserted in the system to the first 180° rotation Pd(II) is converted into Pd(0) and in the fulfill these requirements: (i) a bridging unit that is able to bind second 180° rotation Pd(0) is converted into Pd(II); therefore,

214 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 19. (a) Reversible conformational changes in nickelacarborane Figure 17. Schematic representation of the design principle of a 217 molecular rotary motor based on a biaryl species and a metal redox 11 upon changing the formal oxidation state of the central nickel ion. − cycle. Adapted with permission from ref 216. Copyright 2016 Springer (b) Reversible conformational changes in ferrocene bipyridinium 4+ Nature. species 12 upon redox-controlled intramolecular dimerization of the bipyridinium arms.219 the system could in principle operate autonomously by coupling moieties that can undergo redox-induced dimerization, as of the unidirectional rotation to a redox cycle. illustrated by compound 124+ (Figure 19b).219,220 A similar Sandwich-type compounds, such as metallocenes, metal- approach was employed in compounds comprising a binaphthyl locarboranes, and double-decker porphyrin complexes, have hinge and bipyridinium arms to modulate the binaphthyl been proposed as prototypical species to construct molecular dihedral angle.221,222 Rotary motors of this kind, however, are rotary motors because of the rotation around the metal not available because complete unidirectional rotation has not ion.27,28,33 For example, it was shown that changing the yet been achieved. oxidation state of the nickel ion in carborane 11 (Figure 19a) A very interesting family of molecular rotors has been causes reversible switching between the transoid and cisoid proposed in which unidirectional rotation is supposed to be conformations.217,218 Another strategy to achieve redox control powered by electron-transfer processes involving nanoscale of the rotation around a metal ion in a sandwich complex electrodes (Figure 20).28,223 Such a device would represent a consists of functionalization of the two rotating halves with nanoscale version of the electrostatic motor developed by

Figure 18. Molecular structures and operation mechanism of rotary motor 8, corresponding to the general scheme depicted in Figure 17. Adapted with permission from ref 216. Copyright 2016 Springer Nature.

215 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 20. (a) Structural formula of molecular rotor 13.224 (b) Schematic representation of the mechanism of unidirectional rotation of the rotor powered by electron transfer across a nanoscale junction.223

Benjamin Franklin in 1748. The molecular rotor (e.g., motor without the production of waste. Moreover, it is possible compound 13 in Figure 20a)224 has a piano-stool structure to exploit photons both to cause a transformation on a chemical with a stator designed to be grafted on a surface, a Ru(II) ion as system (i.e., “writing”) and to monitor its state (i.e., “read- − the hinge, and a rotor bearing redox-active ferrocene units. As ing”).126 131 ff shown schematically in Figure 20b, the molecule is placed o - 3.2. Useful Photoinduced Processes center with respect to two facing nanoscale electrodes. A potential difference applied across the junction should cause Light-driven molecular motors base their operation on oxidation of the ferrocene unit nearest the anode, which molecular moieties that following the absorption of photons successively experiences an electrostatic repulsion toward the undergo a sequence of reversible transformations whose cathode. The oxidized unit close to the cathode is reduced, while outcome is the relative movement of one portion of their the next ferrocene unit is oxidized at the anode. Overall, the (supra)molecular structure with respect to another. Therefore, it passage of one electron across the junction should result in is not surprising that the development of photochemically directional rotation of the rotor part of the molecule by one-fifth operated molecular motors is closely related to research on of a turn (Figure 20b). To prevent intramolecular electron reversible light-induced reactions and that most molecular transfer between two ferrocene units, which would compete motors activated by light are actually derived from a rather small with rotation, insulating spacers based on platinum acetylide number of intensely studied compounds that can support units (as in 13)224 or bicyclo[2.2.2]octane225 were introduced reversible and clean photoinduced processes.  into the rotor arms. However, several problems, such as The absorption of photons of opportune wavelength  detection of the unidirectional motion, remain to be solved to usually in the range between 200 and 1000 nm can promote complete this challenging project.223 a molecule to an electronically excited state, which is a transient species with profoundly different physical, chemical, and 3. PHOTOCHEMICALLY DRIVEN MOTORS structural properties compared with the ground state. Because of their large excess of energy, excited states rapidly deactivate to 3.1. General Considerations the electronic ground state through different competitive As discussed in section 1.3.3, nature does not typically use the processes, namely, radiative decay, nonradiative decay, and energy of photons directly to produce mechanical movements chemical reaction.126,127 Among nonradiative decay processes, but rather converts it into chemical fuels (e.g., ATP), which are particularly significant in the present context is electronic energy more suitable energy vectors for powering natural molecular transfer, by which the excited-state energy is transferred to machines. Light energy, however, can bring about large- another molecular unit either intramolecularly (in a multi- amplitude molecular reorganization processes or initiate component or supramolecular assembly) or through a chemical reactions that are conducive to molecular movement. bimolecular encounter. As a result, the energy acceptor becomes Unlike chemical fuels, photoirradiation can power a molecular electronically excited without having directly absorbed a photon

216 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

(see also section 1.2.2). Chemical reactions arising from an excited state include a large variety of different mechanisms such as isomerization, dimerization, additions, rearrangements, proton transfer, dissociation, and redox processes. Photo- reactions can involve large structural changes in a molecular system that, when combined with an appropriate molecular design, can allow light energy to be directly translated into large- amplitude motion or chemical or electrochemical processes to be initiated in single molecules or multicomponent assemblies. Of the different photoinduced processes that can be exploited in principle to operate a molecular device, only a few have actually been applied to molecular switches and motors.128 In fact, to ensure repetitive operation in a molecular machine, clean and fatigue-resistant reactions are required. As discussed in section 1.3, autonomous light-driven molecular motors can be obtained by relying on reversible unimolecular photoreactions. It is therefore not surprising that photoisomerization reactionsa most studied class of photoprocessesare at the Figure 21. Simplified energy profile describing the light- and thermally basis of all light-driven molecular motors and most of the light- 130−132,226−230 induced conversion between the two isomeric forms of a molecular driven molecular devices developed to date. photoswitch. Light-activated natural molecular motors and switches, such as bacteriorodopsin and halorhodopsin ion pumps present in Archea and retinal proteins involved in vision (e.g., rhodopsin), 123 also rely on photoisomerization processes. is promoted only by light irradiation. Stilbenes, azobenzenes, In general, a photoisomerization reaction is a light-induced and spiropyrans belong to the T-type class, while most chemical transformation leading to an isomerization of the diarylethenes are examples of the P-type class. substrate by either bond rotation, skeletal rearrangement, or Usually, quantitative photochemical conversion to either A or atom or group transfer. Although geometrical isomerization can B is prevented because of the overlap of the absorption spectra of also be achieved thermally and catalytically, the peculiarity of the A and B forms, which are both photoreactive (Figure 21). A photochemical isomerization is that the composition of the photostationary state enriched in one of the two forms is photostationary state, in terms of the ratio between the different obtained, whose composition depends on the absorption isomers, is not determined by ground-state thermodynamics but coefficients of the isomers and the quantum yields of the is instead controlled by the excited-state potential energy forward and backward photoreactions at the irradiation surface. In most cases, the absorption spectrum of the isomer wavelength and on the rate constant of the thermal back formed after light irradiation is different from that of the starting reaction.126,127 compound. A color change may thus occur upon photo- The photoinduced E−Z configurational isomerization of irradiation; this is why the adjective “photochromic” or organic compounds around an unsaturated bond is indeed the “photochromatic” is often used to define such spe- most commonly exploited photoreaction in the field of − − − − cies.226 229,231 233 However, some photoisomerizable com- molecular devices and machines.128,130 132,226 232 Representa- pounds that have been widely used for the construction of tive categories of such compounds are alkenes, polyenes, azo molecular machines, such as stilbene, do not strictly adhere to compounds, and imines (Figure 22). this definition because neither isomer absorbs light in the visible The photoisomerization of alkenes and polyenes around a region. More recently the term “molecular photoswitch” has CC double bond (Figure 22a) has attracted much attention come into use to identify molecular species that can be reversibly from theoretical, mechanistic, and synthetic points of view since switched between two states with light.94,95,228,230 This is a most the late 1960s, when Nobel laureate George Wald demonstrated useful addition to the chemical vocabulary that avoids the often that the fundamental process of vision is the photochemical Z−E superfluous or incorrect assumption of visible spectral changes isomerization of the retinal chromophore in rhodopsin.234 upon photoswitching. Because of its centrality for processes promoted by natural light All molecular photoswitches share a number of common and its mechanistic minimalism, retinal photoisomerization is characteristics (Figure 21). In general terms, by irradiation with one of the most investigated unimolecular photoreactions.235 light of proper wavelength (hν), the A and B isomers of a The prototypical example of this class is represented by the E → photoswitchable moiety can be mutually interconverted. In Z photoisomerization of stilbene and its derivatives, which was addition, since in nearly all cases one of the two isomers has a first described in 1946 by A. J. Henry.236 Planar (E)-stilbene is significantly higher thermodynamic stability than the other, a readily converted to the nonplanar Z form upon irradiation with thermally activated (dark) process by which the metastable UV light. The latter, being 12 kJ mol−1 higher in energy isomer (B) reverts back to the stable one (A) can occur. While compared to the E isomer, reverts almost quantitatively back to the photoinduced A → B transformation is usually very fast, the the E form in the dark.231 The photoreaction of stilbene thermal B → A conversion may have a half-life as short as compounds can also be performed by using triplet sensitizers, a nanoseconds or as long as weeks, months, or even hundreds of possibility vastly explored in different light-activated molecular years. Molecular photoswitches can thus be separated in two machines. A photocyclization reaction leading to the formation classes: thermally reversible (T-type), in which the photo- of dihydrophenanthrene-type products, however, can also occur generated isomer thermally reverts to the initial form, and in this class of compounds, whose consequenceif not photochemically reversible (P-type), in which the back reaction appropriately counteracted by functionalization of the stilbenoid

217 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

strong room-temperature fluorescence of the E form. More details will be given in section 3.6.2. The light-induced configurational switching of the NN double bond in azobenzene and related derivatives (Figure 22b) is one of the oldest and most extensively investigated photochromic processes. The Z stereoisomer of azobenzene and the E → Z photoisomerization reaction were discovered in 1937 by G. S. Hartley.243 Since then, the interest in and popularity of the photochemistry of azobenzene derivatives in the scientific community have continuously increased, establish- ing them as a common choice when photocontrol has to be achieved in chemical species and materi- − − − − − als.47 49,51 53,72,73,75,76,78,83 85,94,105,128,130,131,226 232,244 247 The E configuration of azobenzene is ca. 42 kJ mol−1 more stable that the Z form; thus, at equilibrium in the dark, azobenzene is present almost exclusively as its E stereoisomer. The latter is essentially planar, while the Z isomer exhibits a nonplanar structure with a C−NN−C dihedral angle of about 45°.As the E and Z stereoisomers possess similar, largely overlapping absorption spectra in solution, the photostationary states of azobenzenes are mixtures of the two forms with a composition that is strongly dependent on the irradiation wavelength and on the presence of substituents around the azobenzene core.231,232,244 Most of the simple azobenzenes (except those bearing amino or hydroxy substituents) are stable enough in the Z form to be isolated as pure species. In general, the thermally activated Z → E back reaction displays a strong dependence on the substitution pattern, with half-lives of the Z isomer ranging from days for unsubstituted azobenzene to a few microseconds inthecaseofpush−pull azobenzenes. Heteroaryl azo compounds, because of their broad structural diversity that is reflected in their vast range of spectral properties, are emerging as a new class of highly efficient and versatile molecular photoswitches.248,249 Although compounds presenting an azomethine CN double bond, such as oximes, Schiff bases, and hydrazones, have been known to exist in stereoisomeric forms for a long time,250 their photochemical isomerization (Figure 22c) has Figure 22. Main classes of molecular photoswitches based on the E−Z been investigated in detail only in relatively recent times.187,251    isomerization around (a) C C, (b) N N, and (c) C N double This is probably the case because the photogenerated stereo- bonds. isomer, particularly in the case of Schiff bases, is very unstable, and therefore, the fast thermal back reaction hampered the recognition and investigation of the photoinduced isomer- core aimed at frustrating cyclizationis a marked reduction of ization. Indeed, the first reports on the reversible configurational the fatigue resistance. photoisomerization of Schiff bases were conducted at very low A family of compounds displaying a remarkably efficient temperature or in the solid state, where the thermal back photoisomerization reaction around a CC double bond is that reaction is significantly slowed down.252 However, while there is of indigoids and related moieties (Figure 22a). Indigo itself is still much debate on the mechanistic details, nowadays it is not a photoswitch, but alkylation or acylation of the nitrogen recognized that most compounds presenting an azomethine atoms or substitution with sulfur (i.e., thioindigo) leads to linkage are molecular photoswitches.253 These species are − photoswitchable compounds.237 239 All of these derivatives characterized by rates of the (uncatalyzed) thermal back- exhibit absorption bands in the visible region of the spectrum isomerization spreading over more than nine powers of 10: N- that can be tuned by synthetic structural modifications, such that heteroatom derivatives (i.e., oxime ethers and hydrazones) individual derivatives that absorb at nearly any portion of it can present high back conversion barriers and long-term stability, − be prepared.240 242 Moreover, the usually good separation while N-alkylimines and N-arylimines are the least stable. Recent between the absorption bands of the E and Z forms allows clean work, particularly from Aprahamian and co-workers, has and quantitative photoswitching by the choice of proper unraveled a variety of hydrazone compounds exhibiting clean irradiation wavelengths. Usually, the Z isomers of indigo and reversible photoswitching both in solution and in complex compounds possess a very low rate of the thermally activated matrices.95,254 back reaction. Another most interesting and quite unique Besides photoisomerization, another class of photoinduced property that is often exploited as a tool to investigate the processes that has found significant application in the develop- photoreactivity of indigo-type compounds and the operation of ment of molecular devices is that of light-induced proton- molecular devices relying on their photoisomerization is the transfer reactions.255 This is the case because in principle such

218 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review reactions enable photocontrol of pH-responsive processes. One of the first examples of a light-induced reversible pH Three main categories of photoinduced proton-transfer jump was based on a triphenylmethane leucohydroxide, which − reactions can be identified: photoacid (or photobase) releases OH ions upon irradiation with a laser pulse.265 generators, excited-state proton transfer, and proton transfer Nevertheless, the most common design principle of metastable from a metastable state. Photoacid (or photobase) generators256 photoacids and photobases relies on the use of photochromic are molecules that undergo a reaction (e.g., dissociation) under compounds: in fact, the structural rearrangement associated irradiation that results in the release of an acidic (or basic) with the photoisomerization reaction can be accompanied by product. The photoinduced process is chemically irreversible, the emergence of new acid−base properties due to alteration of 266 and photoacids are mainly used as initiators of polymerization the electron distribution or intramolecular interactions. A reactions. In a recent proof-of-concept study, a compound of well-known class of compounds of this kind are the 2- 267,268 fi this kind was employed to operate a chemically driven hydroxyazobenzenes (Figure 24). In the E con guration, mechanical molecular switch.257 In general terms, when the pKa of the excited state of a molecule is different than that of its ground state, the molecule − can undergo excited-state proton transfer.258 260 The actual possibility to release or capture a proton depends on the competition among all of the processes taking place in the excited state.261 A proton transfer back to the conjugate base (or from the conjugate acid) in the ground state resets the systems, thus enabling reversible and cyclic operation. Photoinduced proton transfer is a common process in nature123 and has also been widely explored in chemistry and biology.262 For example, the proton released after excitation of the photoacid can be taken up by an acid−base switch, thus triggering its protonation and 263 deprotonation reactions. The key requirement is that the pKa of the switch is smaller than that of the photoacid in its ground state and larger than that of the photoacid in its excited state. Nevertheless, it is practically difficult to achieve large pH shifts with excited-state photoacids because of their fast relaxation to the ground state. Moreover, the mechanical movements of the machine should be faster than the reverse proton transfer Figure 24. Molecular structures of three classes of metastable state reaction to the ground-state conjugate base. Indeed, the large photoacids: 2-hydroxyazobenzene,268 merocyanines269 and tricyano- difference between the time scales of excited-state processes and furans.270 long-range molecular movements has to date prevented the ff e ective application of excited-state photoacids to operate the acidity of the phenol unit is decreased by the hydrogen- molecular machines. bonding interaction with the nitrogen atoms; this interaction is A metastable state photoacid (or photobase) is a stronger acid lost upon E → Z isomerization, which thus causes an increase in (or base) with respect to the thermodynamically stable species. the acidity of the compound. A general principle proposed for The frame is similar to that discussed earlier for excited states, the design of metastable photoacids consists of an electron- but the lifetime of the metastable species is long enough to allow accepting unit and a weakly acidic nucleophilic moiety its accumulation. Therefore, one can obtain a pH jump large connected by a double bond: upon E → Z isomerization a enough to affect other acid−base-responsive species present in nucleophilic reaction takes place between the two units, with the same solution (Figure 23). The metastable photoacid (or generation of a highly acidic metastable form.264 In this frame, photobase) reverts to the stable species in the dark through two classes of molecules have gained attention for their reverse proton transfer with a half-life that can range from exploitation as photoacids, namely, merocyanine-based spe- seconds to hours.264 cies269 and switches based on the tricyanofuran unit270,271 (Figure 24). Merocyanine compounds have been employed in several examples of signal communication between molecular switches according to the scheme depicted in Figure 23.272,273 With an appropriate selection of molecular components, the photo- induced proton exchange between merocyanine species and pH- controlled switches has been exploited to implement logic functions274,275 or memory elements.276 Credi, Raymo, and co- workers used a metastable photoacid to operate a molecular machine, showing that the threading−dethreading of a non- photoresponsive calixarene−bipyridinium pseudorotaxane277 Figure 23. Schematic representation of the coupled operation of a ≪ could be controlled by light via intermolecular proton transfer metastable photoacid (outer cycle; pKa,BH pKa,AH) and a pH- 278 responsive switch (inner cycle). The “forward” and “backward” involving a merocyanine species. The process is reversible, pathways of the overall switching cycle are shown in red and green, and unlike the operation of the same machine by addition of respectively; dashed lines denote the intramolecular proton transfer acid−base reactants, waste products are not generated upon processes that enable the communication of the two systems. cycling. With the same strategy, by an appropriate selection of

219 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 25. (a) Structural formulas of axle 14+ in its E,E configuration and DB24C8 ring 15. (b) Structural formulas and schematized representations of axle 16+ in its E and Z configurations and ring 17. (c) Schematic operation mechanism and simplified potential energy profiles, as functions of the ring− axle relative position, for each step (gray solid arrows) of the directional light-activated threading−dethreading motion (processes 1, 2, 3, and 4) of the ring and axle components. Dashed lines indicate processes that are kinetically prevented. The orange circular arrow shows the directional flux of species relevant in the operation of the system under steady-state out-of-equilibrium conditions.291,293 the photoacid, rotating hydrazone-based switches279 and an signals with a distinct photoswitch rather than integrating a acid−base-driven molecular shuttle280 could be operated. These photoresponsive unit into the device.272 examples demonstrate the feasibility of such a general approach It is well-known that the excess energy of an electronically for activating a non-photoactive molecular machine with light by excited state can be used to transfer electrons.126,127 The fact exploiting the intermolecular communication of chemical that excited states are generally stronger oxidizing and reducing

220 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review agents with respect to the ground state is at the basis of photoactive cyclopentyl moiety (Cp)292 (Figure 25b), which photoinduced electron transfer processes. These processes exhibits a threading rate through the macrocycle that is imply the interaction of the excited state with an electron intermediate between those of the Azo unit in the E and Z donor or acceptor component, which can either be intra- configurations. molecular in a supramolecular assembly or require a bimolecular Kinetic measurements proved that the slippage rate of the ring encounter of separated partners. Indeed, as for excited-state over the Cp end is nearly 2 orders of magnitude slower than that proton transfer reactions, the charge transfer event is in over the E-Azo end of (E)-16+, while it is still considerably faster competition with other processes taking place in the excited than that over the Z-Azo moiety of (Z)-16+. Despite this state, including primarily back electron-transfer. Most exploited observation, in acetonitrile at room temperature the photo- candidates for the role of photosensitizers in light-induced isomerization of the Azo unit of 16+ did not affect the affinity of electron transfer are transition metal complexes because in many the axle for the macrocycle; hence, the dissociation of ring 15 instances they are excellent chromophores, exhibit tunable and from the axle could not be obtained solely by light irradiation. A reversible redox properties, and possess long-lived (and often second pair of chemical stimuli had to be employed in order to emissive) excited states.281 As noted above, however, the complete a directionally controlled threading/dethreading structural rearrangements associated with the operation of cycle, which enabled the directionally controlled relative molecular machines are typically slower than excited-state translation of the components but prevented the realization of processes, and their efficient competition with the relaxation to an autonomous operating cycle. the ground state by back electron-transfer is a challenge. Hence, To improve the system, in order to achieve autonomous light- the latter process must be slowed down or, in a limiting case, driven operation, ring 15 was replaced with an analogous but totally prevented. For an analysis of this problem and its strongly fluorescent macrocycle (compound 17 in Figure influence on the operation of the molecular machine, see the 25b),293 with the dual aim of (i) enhancing the stability discussion on compound 36+ in section 1.3.3. Several studies in difference of the E and Z pseudorotaxanes and (ii) enabling the which redox-active mechanical molecular switches based on study the self-assembly process by luminescence spectroscopy, a rotaxanes and catenanes are operated by light, taking advantage more sensitive technique than NMR spectroscopy. To further of photoinduced electron transfer, have been reported in the strengthen the ring−axle interactions, dichloromethane was − − literature.132 136,144,282 288 used as the solvent instead of acetonitrile. As anticipated, these − 3.3. Supramolecular Pumps rather simple changes enabled an increase in the ring axle affinity by almost 3 orders of magnitude. Remarkably, the As discussed in section 2.3, the relative movement of the ring association constant of 17 with (E)-16+ turned out to be about 4 and axle components feasible in (pseudo)rotaxane-type times larger than that with (Z)-16+, while the relative values of architectures has been recently explored by different research the rate constants and thus the energy barriers were unvaried. groups for the construction of artificial supramolecular pumps. Hence, in the system composed of axle 16+ and ring 17, In order to make such a device work using light as the sole source photoisomerization of the Azo unit of the axle is able to switch of energy, a photoactive moiety has to be installed in one of the simultaneously both the kinetics and thermodynamics of the components of the (pseudo)rotaxane architecture, such that its self-assembly process of the two components. light-induced transformation influences both the kinetics and Under light irradiation, the system operates as a Brownian thermodynamics of the ring−axle interaction. The scarcity of ratchet driven by photon energy that directionally transports reported systems that conform to this scheme of operation is a rings from one end of the axle component to the opposite end, as clear indication of its challenging realization. represented in Figure 25c. During a cycle, at the start axle (E)- One of the most popular recognition motifs employed to 16+ and ring 17 efficiently self-assemble into the pseudorotaxane build (pseudo)rotaxane-type architectures is that constituted by architecture [17⊃(E)-16]+ (Figure 25c, process 1). The a crown ether encircling a secondary ammonium cation.289 threading of the macrocycle occurs preferentially from the E- Venturi, Credi, and co-workers reported that the kinetics and Azo end of the axle. Irradiation of the E-Azo unit of [17⊃(E)- thermodynamics of the self-assembly process that leads to the 16]+ to yield [17⊃(Z)-16]+ (Figure 25c, process 2), results in formation of a pseudorotaxane between the secondary two simultaneous effects: a reduction in the affinity of 17 toward ammonium axle 14+ and dibenzo[24]crown-8 (DB24C8) ring the Am station and an increase in the dethreading barrier at the 15 (Figure 25a) can be efficiently controlled via photo- Azo end of the axle. The reduced stability of the complex isomerization of the azobenzene units attached at both ends of [17⊃(Z)-16]+ forces the ring to slip past the Cp end, thus 14+.290 Specifically, photoswitching of (E,E)-14+ to (Z,Z)-14+ exiting the opposite side from which it had threaded initially results in both destabilization of the pseudorotaxane complex (Figure 25c, process 3). Most important, since both isomers of and a large decrease in the threading−dethreading rate the axle, namely, (E)-16+ and (Z)-16+, are photoreactive and constants. Moreover, because of the high fatigue resistance absorb in the same spectral region, another photon of the same characteristic of azobenzene photoswitches, the process is fully wavelength can trigger the Z → E photoisomerization of 16+, reversible by irradiation with visible light or by heating. Thus, thus restoring the initial state and completing the cycle (Figure (E)-azobenzene was proved to operate as an efficient photo- 25c, process 4). induced inhibitor and negative catalyst for the self-assembly of Upon light irradiation an out-of-equilibrium stationary state is ring 15 with axle 14+. reached, which establishes a clockwise net flux of species along Building on these preliminary results, the nonsymmetric axle the closed network of reactions (orange arrow in Figure 25c) 16+ (Figure 25b) was synthesized with the objective of that continues as long as photons are absorbed. Hence, in this developing a system in which the ring would be forced to system under constant illumination, light energy powers and thread through the axle by following a specific direction.291 controls not only the nanoscale directional motion of the ring Indeed, axle 16+ accommodates a secondary ammonium station and axle components (unidirectionality) but also the macro- (Am) enclosed between an azobenzene unit (Azo) and a non- scopic flux of the species along the closed reaction network

221 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

(termed “monodirectionality” in section 3.6.2). It is worth becomes oxidized (process 3), and the reduced macrocycle noting that the autonomous and out-of-equilibrium operation of dethreads unidirectionally (process 4). Finally, ptz+ takes an this system is possible thanks to what is usually considered one electron from the free reduced CBPQT (process 5), thus of the major shortcomings of azobenzene photochromic regenerating the reactants, which upon unidirectional threading compounds, that is, the spectral overlap between the E and Z (process 6) regenerate the starting pseudorotaxane, and another stereoisomers (see section 3.2). working cycle can begin. The dethreading process is in Interestingly, it was highlighted that the specific photo- competition with the back electron-transfer reactions from the 3+ + induced ratcheting mechanism depends on the irradiation reduced and still complexed CBPQT to [Ru(bpy)3] or ptz . wavelength employed to induce the isomerization of the Azo Therefore, key requisites for efficient operation of the motor 294 λ 2+ unit of the axle. If light with a wavelength > 400 nm is would be fast photoinduced electron transfer from [Ru(bpy)3] 3+ employed, the system operates according to an energy ratchet to CBPQT and fast redox reaction between [Ru(bpy)3] and mechanism wherein the symmetry-breaking element that ptz (processes 2 and 3, respectively). Electrochemical experi- enables the autonomous operation is the difference in the ments on model compounds and on the pseudorotaxane + association constants of the ring−axle complexes [17⊃(E)-16] indicate that the dissociation of the reduced CBPQT occurs ⊃ + and [17 (Z)-16] . Conversely, if irradiation is conducted at on the millisecond time scale. This process should be faster than 365 or 287 nm, the system operates according to a combination the recombination between ptz+ and the reduced CBPQT. of energy and information ratcheting since at those wavelengths The operation of the supramolecular pump was investigated ffi the photoisomerization e ciency of the axle depends on by following the absorption changes at 520 nm, where a charge whether it is surrounded by the ring. It should also be noted, transfer band arising from the interaction between CBPQT and however, that the work done by the pumping motion is rapidly DNP is diagnostic for the presence of the pseudorotaxane ff wasted by the free di usion of the rings in the homogeneous complex. After 5 min of irradiation with a laser at 450 nm (light solution. Nevertheless, the structural and synthetic simplicity of mainly absorbed by the Ru photosensitizer), a small decrease in the components is expected to favor further development of this 295 this absorption band was observed; when the irradiation was architecture toward more advanced structures capable of stopped, the band slowly recovered until the original spectrum generating concentration gradients or to transport chemical 205 296 was obtained. These observations can be interpreted by species along predetermined pathways. assuming that after a fast photoinduced electron transfer process The only other reported example of a light-activated that generates the reduced pseudorotaxane and ptz+, dethread- supramolecular pump is represented by the redox-activated + 4+ ing takes place followed by slow rethreading after charge system composed of axle 5 and ring 4 (CBPQT), which was recombination. Unfortunately, key experiments in support of the described earlier in section 2.3, when operated by photoinduced mechanism shown in Figure 26, such as the observation of the electron transfer from [Ru(bpy) ]2+ (bpy = 2,2′-bipyridine) in 3 transient electron transfer products Ru(bpy) 3+, ptz+, and the presence of phenothiazine (ptz) as an electron relay (also see 3 reduced CBPQT and a kinetic investigation of the charge section 1.3.3).205 The proposed operation mechanism is recombination between the two latter compounds, were not schematized in Figure 26: Upon irradiation of [Ru(bpy) ]2+ 3 performed. with visible light (process 1), intermolecular electron transfer Also in this case, light energy can drive the system away from from the long-lived 3MLCT state of the ruthenium complex to thermal equilibrium while forcing the unidirectional relative ring 44+ occurs (process 2). The photogenerated [Ru(bpy) ]3+ 3 motion of the components, and this is the only example to date species is reduced back to [Ru(bpy) ]2+ by ptz, which in its turn 3 of a molecular motor that relies on photoinduced electron transfer. However, the delicate sequence of bimolecular reactions and the concentration dependence of the operation mechanism could hamper its practical application and fatigue resistance. In principle, the pump could be operated autonomously, but the very slow rethreading process would limit the turnover frequency. 3.4. Molecular Walkers In the past few years, the large number of bipedal motor proteins found in nature belonging to the myosin, dynein, and kinesin superfamilies that “walk” down intracellular tracks to perform essential tasks in a variety of key biological processes in living − cells2 6 have inspired research on analogous artificial systems.297 Although the mechanistic details at the base of the operation of natural “walking” motors are still not completely understood and their complexity precludes mere replication, the principal design paradigms they have in common with other types of molecular Figure 26. Proposed mechanism for the photochemically triggered motors have been identified.298 First, a molecular walker has to operation of the redox-driven supramolecular pump based on 4+ + be processive; that is, it should always remain bonded to the macrocycle 4 and axle 5 shown in Figure 12. The inner scheme track during its journey. In other words, the walking sequence depicts the photoinduced electron transfer cycle involving [Ru- 2+ must be repeated continuously with the walker never getting (bpy)3] as the photosensitizer and phenothiazine (ptz) as the electron relay, while the outer scheme shows the unidirectional detached from the track. Moreover, the motion along the track threading and dethreading reactions. Adapted from ref 205. Copyright must be directed by a ratcheting mechanism that enables the 2013 American Chemical Society. molecular walker to operate as a motor and not as a randomly

222 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 27. (a) Molecular walker (red) that moves along a four-station molecular track (stations are colored in green and blue) in response to (1) acidification and (2) chemical reduction and oxidation. An irreversible redox process (2) transports the walker predominantly to the right side of the track in compound 18 (away from the minimum-energy distribution).100 (b) Light-driven small-molecule walker that moves along a four-station molecular track in response to the ring strain between the walker (red) and the track induced by the photoisomerization of the stilbene linker group. The reaction sequence transports the walker from the left end to the right end of the track in compound 19; exchanging steps (2) and (4) causes the walker to be transported preferentially in the opposite direction.305 The two numbers used in the descriptors of the molecules indicate the stations to which the walker is linked. diffusing system. Finally, a highly desired property for a walker is internal aldehyde and disulfide footholds of the track of the the ability to process its “fuel” autonomously (see section 1.3). previously described chemically powered walker system. Several examples of synthetic DNA-based walkers have been The key to achieving directionality lies in photoisomerization − reported299 302 that, thanks to the structural flexibility and of the stilbene unit, which allows the introduction of significant highly predictable properties of nucleic acids,303 fulfill all of the ring strain in the constitutional isomer in which the walker unit design elements detailed above. Conversely, fully artificial bridges the stilbene linkage (Figure 27b). E → Z isomerization walkers based on small molecules are relatively rare. The design provides a driving force for the walker to step onto the central → strategies that can be employed to realize light- or chemically stilbene unit, while subsequent Z E isomerization causes a fueled small-molecule walkers have been rationalized and majority of the walkers to move away from the stilbene group in − reviewed.304 However, despite the intense research on this a direction determined by which foot track interaction is type of system in the past decade, fully artificial molecular labilized next. The overall direction in which the walker motion walkers with autonomous operations are still unrealized. occurs is thus dependent on the sequence of the orthogonal fi applied stimuli: acid or base, which controls the dissociation of a The rst small-molecule walkers with the ability to operate in “ ” a processive, directional, and repetitive manner were described foot of the walker from the track, and UV light or visible light by Leigh and co-workers (Figure 27).100,305 They are based on a (plus iodine), which controls the isomerization of the stilbene molecular track with four attachments and a walker unit with unit to increase or decrease the ring strain between the walker and the track. two chemically different moieties that can be connected to the The manipulation of the potential energy surface by altering track. Such functional moieties can be orthogonally addressed in the thermodynamic minima via changes in ring strain through such a way that each “foot” acts as a temporarily fixed linkage stilbene photoisomerization and the kinetic barriers by either while the other is engaged in a dynamic covalent exchange base or acid stimuli results in a Brownian energy ratchet reaction. The chemical design is based on a hydrazone unit that mechanism. In particular, the energy that fuels the directional joins the walker to the track and is labile under acidic conditions → fi transport is supplied by the E Z photoisomerization reaction and a disul de bridge as the second connection that through an of the stilbene unit by establishing a significant configurational fi irreversible redox disul de exchange reaction transports the strain in the track. The other three stimuli are all under walker predominantly to the right-hand side of the track. The thermodynamic control and dissipate the energy stored in the alternation between acidic conditions and the redox sequence strained configuration in order to achieve the desired directional forces the two-legged molecule to walk along the track with a migration of the walker portion of the molecule. significant directional bias by a Brownian information ratchet This system is the first reported example of a molecular walker mechanism (see section 1.2). powered by light, with the added feature that its walking Building on this result, Leigh and co-workers developed the direction can be controlled by reversing the sequence of stimuli. first light-driven small-molecule walker, which is endowed with These two combined features, which are not present in natural the unique possibility for the walker unit to move in either systems, represent a clever demonstration of the potential that direction along a four-foothold track.305 This result was achieved well-designed artificial systems can attain. Besides these valuable by installing a photoisomerizable stilbene moiety between the characteristics, it should also be noted that the motor is slow and

223 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review inefficient, with only a modest directional bias. Furthermore, as the track is short and relatively flexible, isomers can be formed in which the walker unit could bridge nonadjacent binding sites. Future studies on small-molecule walkers are likely to focus on new mechanisms for improved directional bias, different walker−track binding chemistries, and walker units that can migrate along tracks autonomously. Another stimulating task is the design of new tracks that are rigid or polymeric, have junctions, and/or may be tethered to surfaces. 3.5. Catenane Rotary Motors As discussed in section 1.2.1, the topology inherent to catenanes presents key advantages for the realization of molecular motors compared with other supramolecular architectures. In fact, the interlocking of the ring components in a catenane enables ratcheting of the circulation of one ring with respect to the other, and even if a steady state in the distribution of the components is reached, directional motion can continue indefinitely without the need to compartmentalize the system. In a landmark study, Sauvage and co-workers observed the redox-controlled circum- rotation of the molecular rings of a [2]catenane;141 later, in collaboration with Balzani and co-workers, photochemically driven operation was also realized.283 This system, however, is not a motor because of the absence of directionality in the motion. In 2004 Leigh and co-workers designed and realized the first light-fueled catenane rotary motor that accomplishes directional biased circulation of one ring with respect to another via a photoactivated Brownian ratchet mechanism.212 The system exploits a rather complex design based on a [3]catenane architecture, in which the presence of a third macrocycle helps in restricting the rotational freedom of the circumrotating rings (Figure 28). In catenane 20, the larger macrocycle acts as a track for the two interlocked smaller rings by incorporating four different stations: fumaramide (A, green), methyl-substituted tertiary fumaramide (B, red), succinamide (C, orange), and amide (D, purple). The four binding sites on the large macrocycle were selected to display a relative affinity for the smaller amide macrocycles in the order A > B > C > D (Figure 28). As the fumaramide station A is positioned right next to a benzophenone unit, the isomerization of this station can be Figure 28. Directional circumrotation in [3]catenane 20 upon photosensitized by energy transfer, thus permitting the use of sequential light and chemical stimulation: (1) photosensitized light of longer wavelength than that required for the non- isomerization of the fumaramide station (A, from light green to sensitized photoisomerization of the fumaramide station, B. black) upon irradiation with 350 nm light; (2) photoisomerization of This design permits selective switching of the binding affinities the tertiary fumaramide station (B, from red to pink) upon irradiation of the A and B stations by irradiation with light of different with 254 nm light; (3) back conversion of the A and B stations upon wavelengths. heating or by irradiation with light in the 400−670 nm range in the Initially, one of the macrocycles (Figure 28, blue ring) resides presence of a catalytic amount of Br2. Adapted with permission from ref on the strongest binding station, A, while the second macrocycle 38. Copyright 2017 Royal Society of Chemistry. (purple ring) encircles the second most favored station, B. The photosensitized selective E → Z isomerization of station A with ring. Thermal back-isomerization, either in the presence of a 350 nm light weakens its interactions with the macrocycle and catalytic amount of ethylenediamine or by irradiation with 400− promotes the translocation of the latter toward the succinamide 670 nm light in the presence of a catalytic amount of Br2, restores ester station, C (Figure 28, process 1). The presence of the the initial configuration of the fumaramide stations (Figure 28, second macrocycle residing around the tertiary fumaramide process 3). station, B, forces the translocation of the first ring (colored in It should be noted that in the course of this sequence the purple in Figure 28) to occur in an anticlockwise direction by position of the two macrocycles is swapped; hence, a second acting as a kinetic barrier to circumrotation in the opposite sequence of the same stimuli is necessary to fully reset the system direction. Subsequent selective photoisomerization of the and bring the macrocycles back to their initial positions by fumaramide station, B, with 250 nm light causes the second completing a full directional rotation. In [3]catenane 20, the macrocycle to shuttle to its final resting position encircling the combined control of the binding affinities of the stations by light amide station, D (Figure 28, process 2). Again, the presence of a irradiation and of the kinetic barrier presented by one second macrocycle causes directionality in the movement of the macrocycle to the other allows the directional rotation; in

224 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 29. Photochemically and chemically driven directional circumrotation in [2]catenane 21. A and B indicate the fumaramide and succinamide stations, respectively. C and D indicate the (tert-butyl)dimethylsilyl and triphenylmethyl kinetic barriers, respectively. Adapted with permission from ref 212. Copyright 2004 American Association for the Advancement of Science. other words, a “follow the leader” process is established in which pathways can be broken, resulting in directionality in the relative one small ring controls the direction of circumrotation of the motion of the two rings. other. In the starting state, the small ring encircles the fumaramide A rotary motor based on a simpler [2]catenane architecture station, A. Upon E → Z isomerization promoted by 254 nm light and utilizing an alternative mode of operation was later reported and subsequent removal of the silyl protecting group, the small by the same group.212 In compound 21 (Figure 29) the larger ring moves in a clockwise direction to encircle the succinamide ring presents only two binding sites for the smaller ring: a station. Reattachment of the silyl protecting group and photoisomerizable fumaramide station (A) and a succinamide subsequent back-isomerization of the A station followed by moiety (B). Station B is bordered by two bulky protective removal of the trityl group results in a half-turn of the small ring groups that act as kinetic barriers for the movement of the ring that ends up surrounding the B station. Finally, tritylation of the and can be orthogonally detached and reattached: a (tert- free hydroxy group restores the initial state, thus concluding a butyl)dimethylsilyl group (C) and a triphenylmethyl group (D). full clockwise rotation powered by light irradiation and two The ratcheting balance-breaking operation is based on the orthogonal chemical stimuli. By inversion of the sequence of sequential application of successive light and chemical stimuli. In silylation and tritylation protection/deprotection reactions, the analogy with the previously described [3]catenane, light input motion of the smaller ring can be reversed, affording induces the E → Z photoisomerization of the fumaramide counterclockwise circumrotation. station, A, thereby changing the relative binding affinities of the Catenanes 20 and 21 are the only examples of light-powered small ring for the two stations in favor of station B. Two rotary motors based on mechanically interlocked molecules. orthogonal chemical inputs attach or detach the bulky protective Although both systems present some sophisticated features, groups around station A, thus switching the kinetic barrier such as the possibility to invert the direction of rotation, the experienced by the small ring during its movement along the complex sequence of stimuli required to operate them limits the larger “track” ring. By the application of these inputs in the efficiency of these systems and prevents autonomous operation. correct sequence, the degeneracy of the two circumrotation Another problem is related to the exploitation of the ring

225 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review circumrotation to extract useful work or perform functions, ment of motors with made-to-order characteristics because of because it is not easy to imagine covalent modifications of the their straightforward synthesis.213 components (e.g., for attaching a cargo moiety or linking the 3.6.1. Overcrowded Alkenes. The first example of a light- motor to a surface or to the backbone of a polymer) that would driven single-molecule motor capable of performing repetitive not block the movement. Surely this type of light-driven unidirectional 360° rotation, thus converting light energy into a molecular motor is still underdeveloped, and there are controlled directional rotary motion, was reported in 1999 by opportunities for the design and construction of new prototypes Feringa and co-workers (Figure 31).309 The motor system is relying on more practical and efficient operation schemes. 3.6. Molecular Rotary Motors Rotary motion is intrinsic at room temperature in single bonds, but directional control of this motion is a highly challenging task. Initial attempts to develop molecular rotary motors were based on compounds endowed with sterically bulky groups and nonsymmetric moieties such that the free rotation around a single bond could be forced to occur along a preferential direction, in a way similar to a geared pawl device.98 This system, which is the molecular implementation of Feynman’s “ratchet and pawl” paradox,306 cannot lead to directional motion because it lacks a ratcheting mechanism supported by an energy source.307 In an outstanding proof-of-principle study, Kelly and co-workers introduced a chemically powered ratcheting step and demonstrated the occurrence of unidirectional 120° rotation.308 Complete and repetitive unidirectional rotation, however, remained an elusive goal. A true molecular rotary motor was eventually developed by controlling the rotation around a double bonda fact that seems counterintuitive since rotation around double bonds is Figure 31. Structure and mechanism for unidirectional rotation of restricted. It is well-known, however, that light can cause such a Feringa’s first-generation light-driven molecular rotary motor 22.309 rotation in an extremely efficient manner in photoisomerization Steps (1) and (3) are E/Z photoisomerization steps, and steps (2) and processes (see section 3.2). Definitely, the totality of present-day (4) are thermal helix inversion (THI) steps. The “stator” and “rotor” light-powered molecular rotary motors is based on the moieties are colored in black and red, respectively. photochemically driven E−Z isomerization of carbon−carbon or carbon−nitrogen double bonds. Photoisomerization is based on chiral overcrowded alkene 22 featuring a carbon− combined with specific stereochemical elements that, by carbon double bond connecting two identical halves. The steric breaking the symmetry of the potential energy surface, cause a hindrance between the two rotating halves, installed in the directional bias in the relative sense of rotation of a “rotor” with system by the relatively short double bond, forces an out-of- respect to a “stator” portion of the molecule.213 plane arrangement of these two portions, thus conveying a Three main classes of molecular rotary motors have been helical shape (P or M) to the molecule, which proved to be a 310 developed in the last 20 years (Figure 30): (i) overcrowded fundamental prerequisite for the operation of these systems. For each enantiomer of the first-generation molecular motor, four different stereoisomers exist, which can be interconverted following a sequence of four discrete alternating reactions activated by light and heat that results in the unidirectional rotation around the carbon−carbon double bond (the rotation axle). Starting from the stereoisomer (P,P)-(E)-22,light irradiation at 280 nm induces E → Z photoisomerization of the double bond, resulting in the inversion of the helicity and formation of (M,M)-(Z)-22. This species is metastable because of the strain caused by the methyl substituents that are forced in an equatorial conformation. The excess energy present in (M,M)-(Z)-22 is released in a thermally activated step in the ground state in which one half of the molecule flips over the Figure 30. Chemical structures of the three main classes of molecular other half, thus inverting the helicity of the molecule and rotary motors. The “stator” and “rotor” moieties are colored in blue and 38 reorienting the methyl groups in their energetically favored red, respectively. position, affording (P,P)-(Z)-22. This thermal relaxation reaction, named “thermal helix inversion” (THI), is practically alkenes, which represent the first and most investigated family of irreversible because of its large driving force and is responsible molecular rotary motors and one of the most advanced and for the bias in the rotation direction. A second photo- extensively applied classes of molecular motors in general (see isomerization reaction transforms (P,P)-(Z)-22 into the section 5);68 (ii) hemithioindigos, which have several analogies metastable (M,M)-(E) form, which undergoes a second THI with the previous class but can be natively powered with visible step and concludes a 360° cycle of rotation around the carbon− light and exhibit extremely high rotational speed;239 and (iii) carbon double bond by reforming the starting stereoisomer imines, which are highly promising candidates for the develop- (P,P)-(E)-22. This mechanism of operation shows an elegant

226 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 32. Simplified energy profile for the 360° rotation of the first-generation overcrowded alkene rotary motor 22. Steps (1) and (3) are the E−Z photoisomerization steps, while steps (2) and (4) are the THI steps. The “stator” and “rotor” moieties are colored in black and red, respectively. Adapted with permission from ref 38. Copyright 2017 Royal Society of Chemistry.

Figure 33. (left) Cartoon representation of the general structure (“stator” in blue, “rotor” in red) of light-activated rotary motors of the overcrowded 38 ff ff ° alkene family. Right: structural variations of the di erent motor generations and their e ect on t1/2 (at 25 C) of the THI processes, which is inversely related to the rotational speed.213 interplay between the dynamic helical chirality established in the the two rotating halves. As shown schematically in Figure 32, the molecule by the bulky substituents attached to the double bond configuration of the stereogenic centers biases the direction of and the fixed point chirality of the stereogenic centers decorating rotation during the photoisomerization step that inverts the

227 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 34. Structure and mechanism for unidirectional rotation of the fourth-generation light-driven molecular rotary motor 29 in the presence of the chiral guest 30. Adapted from ref 315. helicity of the molecule, while the irreversible energetically move in the same direction, in analogy to the wheels of a car downhill THI ensures that the motor returns to its stable form, connected by the axle. Besides reducing the amount of structural from which it can be excited again, leading to autonomous light- asymmetry required to achieve unidirectional rotation, in this driven operation.309 generation of motors the computationally determined THI The main shortcoming of the first-generation molecular ratewhich regulates the rotational speedis one of the motor is that the activation barriers for the two THI steps are not highest ever reported for an overcrowded alkene molecular equal (Figure 32). Thus, the rotational motion proceeds with an motor, thus making compound 28 one of the fastest rotary irregular speed, and one half of the 360° rotation can be motors developed to date. Moreover, the unique rotational considerably slower than the other, depending on the difference dynamics displayed by this generation of motors could in between the activation energies of the two THI steps. In fact, principle be applied to obtain a directional movement on a because of the low rate of the (M,M)-(E) → (P,P)-(E) surface, fostering the development of a new generation of transformation at room temperature, motor 22 could perform autonomous light-powered nanocars.116,313 full rotation cycles in an autonomous fashion only at In a continued effort to reach a minimal amount of chiral temperatures higher than 60 °C.310 The second-generation information for dictating the direction of rotation in over- overcrowded alkene molecular motors developed by Feringa crowded alkenes, Feringa and co-workers developed a new type and co-workers addressed this issue by replacing one of the two of molecular rotary motor that is completely devoid of halves of the first-generation motor with a symmetrical moiety stereocenters in the photoactive portion of the system.315 In (e.g., compounds 25−27 in Figure 33).311 While the same this “fourth-generation” motor (compound 29 in Figure 33), the mechanistic steps illustrated in Figure 32 account for the preferential direction of rotation is enforced by a chiral guest functioning of the second-generation motors, the simple and molecule that can bind non-covalently to a light-activated elegant structural modification results in very similar barriers for switch. In other words, it is a supramolecular transfer of chirality the two THI steps, allowing more uniform and controllable from the optically active guest that induces the unidirectional rotational motion. Moreover, the new overcrowded alkene rotation around the double bond of the photoswitchable molecular motors proved that the presence of a single receptor. Under the operational conditions (Figure 34), stereogenic element is sufficient to achieve unidirectional irradiation of motor 29 with 365 nm light results in equal rotation.312 rates of formation of the P and M stereoisomers of the The amount of “chiral information” necessary to achieve photoswitchable moiety at the photostationary state. Binding of directionally controlled rotation was further reduced in the so- chiral phosphate anion 30 induces the preferential formation of called third generation (compound 28 in Figure 33).313,314 The one of the helical isomers, (P)-(Z)-29⊃(S)-30, over the other, design of the third generation is based on two second-generation (M)-(Z)-29⊃(S)-30, by a THI reaction. In this situation, the overcrowded alkene motors joined together in such a way that reverse Z → E photoisomerization takes place predominantly the single stereocenter present in the two motors becomes a from the (P)-(Z)-29⊃(S)-30 isomer, thus concluding a full pseudo-asymmetric center in 28, thus making the whole cycle with a net unidirectional rotation of the two halves of the molecule achiral. The mode of operation is analogous to two photoswitchable host around the joining double bond (Figure rotary motors operating together; it should be noted that the two 34). rotor moieties rotate in opposing directions relative to the The mechanism of operation of the fourth-generation rotary middle stator unit. For an external observer, both rotor parts motor closely resembles that of the first-generation one:

228 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review ultimately, it is the formation of a metastable diastereomeric contrasting results suggest that while the mechanism of supramolecular complex during the photochemical step that operation is at first sight similar for first- and second-generation drives the unidirectional rotation. Since the direction of rotation motors, the details of the rotation mechanisms in the two is enforced by the chirality of the guest, which can be easily generations of motors are different, and their comprehension exchanged in situ with a guest of opposite chirality, this deserves further research efforts. generation of motors offers the unique possibility to switch the While the dynamic control of the rotational rate by medium sense of rotation of the motor by means of chemical input. effects evidenced unexpected complexities, different systems Numerous studies aimed at increasing the rotational speed of have been developed with the purpose of modulating the the first- and second-generation rotary motors by analyzing in rotational motion with chemical or light stimuli. In the second- depth the effect of structural modifications on the mechanism of generation motor 31 (Figure 36a), functionalized on the rotor − their operation were also carried out.316 318 Since the photochemical isomerization is vastly faster (picosecond time scale) than the THI steps,319 these studies mainly focused their attention on possible ways to reduce the barrier of the thermal steps to increase the rate of rotation. Experimental screening of different substitution patterns, aided by high-level computa- tional studies, culminated in the development of modified first- and second-generation motors that can operate in the megahertz regime. This level, however, does not yet represent the speed limit predicted by theoretical calculations.312,320 Dynamic control of the rotational speed was a successive logical step to obtain a higher level of control in the operation of overcrowded alkene molecular motors. Preliminary investiga- tions proved that the speed of the rotary motors is dependent on the nature of the solvent. In a series of systematic studies on first- generation motors with pendent arms of variable flexibility and length (Figure 35a), it was observed that the dynamics of the

Figure 36. Structures and mode of operation of (a) chemically323 and (b) photochemically325 controllable light-activated second-generation molecular rotary motors.

half with a biphenol moiety, the rotational speed could be decreased by more than 2 orders of magnitude upon complexation with diamine 32.323 The binding of the diamine effectively decreases the rate of the THI step by forcing the rotor portion of the motor into a rigid planar conformation. The 321 Figure 35. General structure and variations of (a) first-generation binding affinity of the amine guest can be tuned by the addition 322 and (b) second-generation molecular motors developed to study the of either methanol or acetic acid, thus allowing the behavior of solvent viscosity dependence of the rotational dynamics. The “stator” “ ” the molecular motor to be reversibly modulated through a and rotor moieties are colored in black and red, respectively. combination of different chemical triggers. Along the same direction, by functionalization of the motor with a crown ether THI steps are a function of both the size and rigidity of the moiety, the rotary speed could be modulated by complexation substituents and the solvent viscosity, while the solvent polarity with different metal cations.324 More recently, in second- plays a minor role.321 Interestingly, analogous studies conducted generation motor 33 bearing a photochromic dithienylethene on second-generation motors decorated with similar substitu- (DTE) moiety attached to its rotor portion (Figure 36b), the ents (Figure 35b) evidenced that for this class of motors the THI possibility of light-gating of the rotational motion was step is independent of the viscosity of the medium and size of the demonstrated.325 The photochromic DTE unit can be switched substituents. The rate of the photochemical step, which was from an open form to a closed form by irradiation with a revealed to be a complex stepwise excited-state reaction by fast different wavelength from the one applied to operate the motor. spectroscopy studies,319 is influenced by the viscosity of the In the closed form (compound 34 in Figure 36b), the DTE solvent but is independent of the size of the substituents.322 This moiety completely inhibits the rotation of the motor unit. While implies that in the second-generation motors the evolution of the detailed mechanism of inhibition of the rotary motion by the the excited state toward the ground state is dominated by closed form of DTE is not completely understood, the result structural changes in the inner core of the motor, without large- achieved is remarkable, representing the first case of a scale reorientation of the motor and its substituents. These phototriggered light-powered molecular rotary motor (see

229 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review section 3.7 for examples of phototriggered chemically powered motor. Furthermore, a large increase in the speed of rotation was motors). Moreover, the extension of the conjugation brought by observed that was shown by theoretical calculations to be the the functionalization with the DTE unit contributes to red- result of slight modifications of the conformation of the stator shifting the wavelength of light used to operate the motor into portion of the motor as a result of metal complexation. Very the visible region. recently it was shown that second-generation rotary motors can In order to employ light-driven artificial rotary motors in also be operated by visible light by modification of the rotor half. biological systems, two key requirements have to be fulfilled: (i) For example, in compounds 39330 and 40331 (Figure 38), the solubility in water and (ii) operation by excitation with light that rotor contains pyrenyl and N-methyloxyindole moieties, can deeply penetrate living tissues without damaging respectively. them.228,245 To reach these goals, first- and second-generation A key aspect of overcrowded alkene motors is their ample motors were rendered water-soluble by functionalization with potential for further chemical modification. This is clearly appropriate hydrophilic substituents (see, e.g., compounds 35 evidenced by the large variety of different structures described so and 36 in Figure 37), and their operation was investigated in far, that enabled not only fine-tuning of their operation but also their application in different chemical environments, encom- passing surfaces, membranes, and nanoarchitectures (also see section 5).332 A recent example is the functionalization of a quartz surface with the second-generation motor 41 bearing a fluorescent perylenebis(imide) (PBI) moiety on the rotor portion (Figure 39).333 Light-driven rotation and fluorescent

Figure 37. Structure of water-soluble molecular rotary motors of the first (35) and second (36) generations.326 The “stator” and “rotor” moieties are colored in black and red, respectively. aqueous buffers, verifying that the modified motors could function also in complex media.326 The operation of second- generation motors has also been demonstrated inside micelles, whose lipophilic core closely mimics the environment present in cellular membranes and other biologically relevant hydrophobic regions. Visible-light-powered rotation in overcrowded-alkene-based motors was first accomplished by triplet sensitization from an appended porphyrin with 530 nm light.327 More recently it was shown that by extension of the aromatic core of a second- generation molecular motor with a dibenzofluorene lower half (compound 37 in Figure 38), the excitation wavelength is significantly red-shifted (down to 490 nm) without impairing the motor function.328 The straightforward design makes extension of the conjugation of the stator moiety a promising and easily applicable strategy to tune the wavelength of the light used to operate this class of motors. In a radically different design, the stator portion of a second- generation motor was substituted with a 4,5-diazafluorenyl coordination motif.329 Upon complexation with bis- Figure 39. Structure of the second-generation molecular rotary motor 41 bound to a quartz surface. The rotor portion (in red) was (bipyridine)ruthenium(II) (compound 38 in Figure 38), the fl rotation process can be driven with visible light with a functionalized with a long rigid tether bearing a uorescent perylenebis(imide) unit (green). Adapted from ref 333. Copyright wavelength of 450 nm. This observation was tentatively 2018 American Chemical Society. attributed to energy transfer from the metal complex to the

Figure 38. Structures of second-generation molecular motors 37,328 38,329 39,330 and 40,331 whose rotary movement can be driven by visible light. The “stator” and “rotor” moieties are colored in black and red, respectively.

230 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 40. Schematic representation of the 3D architecture of a “moto-MOF”. The packing of the crystal, the elementary cell, and the structure of the linkers, tetracarboxylic acid (TCPB), and molecular motor (42) are shown. The stator of the motor (that is, the fluorene unit) is used to bridge the 2D layers constructed from Zn paddlewheel clusters and TCPB, while the rotor moiety (the naphthyl unit) can rotate freely with respect to the other half under light irradiation. Adapted with permission from ref 335. Copyright 2019 Springer Nature.

Figure 41. Simplified energy profile for the 360° rotation of the HTI-based molecular motor 43.3371 and3 are the E−Z photoisomerization steps, while2 and4 are the thermal helix inversion (THI) steps. The “stator” and “rotor” moieties are colored in black and red, respectively. detection were achieved with the multicomponent assembly details of their operation at the single-molecule level in grafted onto an amine-coated quartz substrate.334 Akey unprecedented detail. structural feature of 41 is that the PBI unit is connected to the Very recently, second-generation molecular motors were motor with a rigid tether that is long enough (ca. 3.2 nm) to arranged in a crystalline metal−organic framework (MOF), as prevent photoinduced electron transfer that would impair motor illustrated in Figure 40.335 The motor units were installed in the operation. This system enabled imaging of the unidirectional three-dimensional (3D) structure as part of the organic linker rotation of individual molecular motors on a surface via (compound 42 in Figure 40). A combination of X-ray analysis defocused wide-field microscopy, thus revealing the mechanistic and optical and Raman microscopy provided proof of

231 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review unhindered unidirectional rotation in the solid state, permitted motor and a kilohertz theoretical maximum speed of rotation, by the large free volume of the chosen framework, with a rotary which would be quite remarkable performance. As a matter of speed (estimated from the rate of THI) comparable to that fact, the speed of rotation is limited by the slowest thermal measured in solution. These so-called “moto-MOFs” hold high process (which is the (S,M)-(E)to(S,P)-(E) helix inversion, promise in applications aimed at controlling dynamic functions process 2 in Figure 41) only if the photochemical reactions are in crystalline materials, such as the diffusion of gases and the able to keep the system in the (S,M)-(E) state. Actually, under mass transport of adsorbed molecules, or as miniature light- normal irradiation conditions, because of the low quantum yield powered pumps in microfluidic devices.336 of photoisomerization, the rate-limiting step is the light-driven In summary, the exceptional synthetic flexibility, together population of (S,M)-(E) (process 1 in Figure 41), which reduces with a deep understanding of their functioning, definitely makes the maximum rotation rate to 0.01−1 Hz. All of these results this category of rotary motors one of the most developed and taken together are extremely valuable for the proper design of widely applied classes of light-powered molecular motors in molecular motors. nanoscience (see section 5). A more crowded HTI derivative was also investigated with 3.6.2. Hemithioindigos. The first example of a hemi- conventional spectroscopic techniques at room temperature. thioindigo (HTI)-based molecular rotary motor was designed Indeed, upon insertion of greater steric hindrance on the rotor by implementing additional stereochemical elements to the HTI (stilbene) fragment, the kinetics of rotation can be slowed down, framework (Figure 41):337 a stereocenter on the sulfur atom thus enabling characterization of all four stable states.339 (oxidized to a sulfoxide) and helical twisting around the double An original strategy for developing rotary motors was bond (by introducing steric crowding on the stilbene fragment). implemented with hemithioindigo derivative 44 shown in Therefore, molecule 43 can assume Z and E configurations with Figure 42.340 Also in this case a stereocenter on the sulfur respect to the CC double bond, R and S configurations on the sulfur atom, and P and M helicities around the double bond. The racemic mixtures of S and R enantiomers were analyzed; for the sake of conciseness, only one isomer will be discussed (see Figure 41). The (S,P)-(Z) isomer is the thermodynamically stable form of motor 43, in thermodynamic equilibrium with the (S,P)-(E) isomer, which in turn is the most stable isomer of the metastable E configuration. Irradiation experiments on rotary motor 43 can be summarized as follows: upon irradiation with visible light, (S,P)-(Z) is converted into (S,M)-(E) (process 1 in Figure 41), which upon THI becomes (S,P)-(E) (process 2 in Figure 41). Irradiation of this compound transforms it into (S,P)-(Z) again, but without the formation of the metastable (S,M)-(E). Actually, another metastable state must be formed, i.e., (S,M)-(Z) (process 3 Figure 41), which could not be evidenced experimentally. The two coupled photochemical and thermal reactions consist respectively of 180° rotations, but they follow two different pathways: this result is only compatible with an overall 360° rotation. The operation of the rotary motor under irradiation is schematized by the energy profiles in Figure 41, which were also confirmed by theoretical calculations. Moreover, the theoretical description gives a calculated Figure 42. Molecular structures and interconversion pathways of the energetic barrier for helix inversion from (S,M)-(Z)to(S,P)- 340 “ ” “ ” −1 four stable diastereoisomers of 44. The stator and rotor moieties (Z) of only 5.54 kcal mol , which corresponds to a half-life of are colored in black and red, respectively. 0.75 μsat90°C, a time range not accessible with conventional techniques. In order to get evidence of the elusive (S,M)-(Z) isomer, fast atom and a chiral axis confer asymmetry to the molecule, which spectroscopy measurements and theoretical calculations were can exist in four different states (Figure 42). These isomers differ performed.338 Three important results emerged from that either by the Z (A and B) or E (C and D) configuration or by the complete investigation. First of all, the formation of all four Sa (A and C) or Ra (B and D) axial chirality, and the stable states was experimentally proven. Moreover, theoretical atropisomers are thermally stable. The first consequence is that investigation evidenced that after photoexcitation both (S,P)- all four species can be separated and characterized. Each species, (Z) and (S,P)-(E) can reach triplet states, which then deactivate when irradiated, is converted into the others, following three to the ground state without leading to isomerization; the triplet possible reaction pathways: single-bond rotation, double-bond state of (S,P)-(E) was also evidenced and characterized with isomerization, or hula twist,341,342 i.e., coupled double- and time-resolved spectroscopy. Triplet pathways are in competition single-bond rotations. As an example, isomer A can convert into with the isomerization reactions and are therefore unproductive B via single-bond rotation, to C via double-bond isomerization, for motor rotation. Nevertheless, these pathways are not the and to D via hula twist. Overall, 12 photoreactions could take major factor responsible for reduced performancethe high place, which would interconvert each isomer with all of the quantum yields of the unproductive internal conversions are others. The photochemical quantum yields of all the reactions much more important. Finally, analysis of the kinetic and under irradiation at 442 nm were determined via NMR thermodynamic parameters associated with the operation of the spectroscopy, and the probability of each reaction over the molecular motor established a 95% unidirectionality for this others could then be estimated. In order to operate as a

232 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review molecular motor, at least three steps must be performed without any reversal process (the probabilities of cycles involving more than three steps were low, so such cycles could be neglected). Therefore, eight different three-step cycles (four forward and four backward) can take place: ABC, ABD, ACD, and BCD are the forward cycles, and ACB, ADB, ADC, and BDC are the backward ones. Among all these possibilities, the ABC cycle is the most probable one at 20 °C, with a preference over the other cycles (i.e., monodirectionality) of 81% and 100% unidirection- ality. Nevertheless, the propensities of the different photo- chemical reactions, and therefore the reaction pathway, can be modulated by changing the temperature. In the present system, to improve the monodirectionality (i.e., the preference for one cycle over the others), the probability of the B to C hula twist photoreaction should increase relative to the B to D double- bond isomerization, which is accomplished by decreasing the temperature to −50 °C. Indeed, under those experimental conditions, the monodirectionality of the ABC cycle is 98%. Figure 43. General schemes for the (top) photochemically and (bottom) thermally activated isomerization processes of imines.213 This is an unprecedented result in molecular motors, and it is clearly related to the absence of thermal steps in the sequence of reactions. Thermal steps in molecular motors are usually the exhibit slow thermal E−Z isomerization at ambient temper- ratcheting steps of the unidirectional rotation. Indeed, the ature.346 unidirectionality, speed, and efficiency of the rotary motor Figure 44a shows the structure and operational cycle of the depend on these processes. When the temperature is decreased, imine-based motor 45. Irradiation of (P)-(Z)-45 leads to Z → E these thermal reactions are slowed down or suppressed, and the photoisomerization through rotation around the CN double molecular motor is converted into a molecular switch. This bond, resulting in the metastable (M)-(E) stereoisomer. molecular motor relies on a new strategy and unique rotation Interestingly, it was discovered that this high-energy strained mechanism that is controlled solely by photons. Recently the species relaxes to the more stable (P)-(E) form not through HTI motor was functionalized with thioether feet for attach- pyramidal inversion of the substituents on the nitrogen atom but 343 ment on metal surfaces. rather by a faster ring inversion process reminiscent of the 3.6.3. Imines. Compounds containing a CN double bond, thermal helix inversion observed in overcrowded alkene rotary such as imines, oximes, and hydrazones, combine the features of motors (section 3.6.1). This additional process can occur CC bonds present in alkenes with the fluxional stereo- because of the flexibility of the aromatic skeleton of the stator chemical possibilities intrinsic to a nitrogen atom. Lehn was the portion of the motor, which is able to flip in and out of the plane. first one to hypothesize, in the otherwise deeply explored The successive absorption of a photon triggers another half- chemistry of the CN double bond, the possibility to develop a rotation around the CN double bond to yield (M)-(E)-45, novel class of rotary molecular motors.344 The key aspect was and a final ring inversion step completes a full 360° rotation of identified in the possibility of CN double bonds to follow two the substituents around the double-bond axis. The operation different independent E−Z isomerization pathways depending mechanism proceeds through four distinct steps and is very on whether the configurational switching is initiated by light or similar to that of overcrowded alkene motors. heat. Earlier experimental and theoretical studies indicated that With an extremely elegant modification of the aromatic stator while the thermal isomerization proceeds by an in-plane unit, rigidified by the introduction of a fused benzene ring that nitrogen inversion, the light-induced E−Z isomerization reduces the flexibility of the heptenyl aromatic core, Lehn and proceeds through an out-of-plane rotation around the CN co-workers developed a motor molecule that, despite its double bond (Figure 43).252,253 The distinct trajectories of the similarity with 45, operates in a different fashion.346 Upon thermal and photochemical pathways suggested that a light irradiation, (M)-(Z)-46 (Figure 44b) undergoes Z → E combination of light and thermal energy could lead to a photoisomerization of the double bond through bond rotation; particularly simple and versatile molecular motor. In fact, it was the so-formed high-energy (P)-(E) form undergoes pyramidal argued that under chiral symmetry-breaking conditions, inversion at the nitrogen atom, as ring inversion is now a more achieved by introducing a stereogenic center near the nitrogen energetically demanding path because of the rigidification of the atom, the photoinduced rotation could be forced to occur aryl moiety. The pyramidal inversion proceeds through an in- preferentially along a specific direction (either clockwise or plane rotation that leads to the starting stereoisomer by anticlockwise). Such a photoinduced motion, together with the completion of a 360° rotation in only two elementary steps. thermally activated in-plane isomerization, would result in the Thus, it was nicely demonstrated that fine-tuning of the unidirectional rotation of the substituents attached to the carbon conformational flexibility of the aryl “stator” can alter the and nitrogen atoms around the double-bond axis. Thus, the mode of operation of this class of motors from a four-step directional light-driven rotation in one direction stores energy, sequence of processes (alternating light power strokes and which is then released by thermal nitrogen inversion. thermal relaxation steps via ring inversion) to a two-step The vast amount of research on the chemical properties of sequence (a light power stroke and a thermal relaxation step via CN double bonds helped in the choice of the best nitrogen inversion). combination of substituents to realize this conjecture.345 The It is important to highlight that the possibility of installing a design of the working prototype of the first amine-based rotary wide variety of substituents at the nitrogen and carbon termini, motor was based on diaryl-N-alkylimines, which are known to together with the straightforward synthetic accessibility of

233 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 44. Structural formulas, operating mechanisms, and simplified energy profiles for 360° rotation of imine-based light-driven molecular rotary motors.346 (a) Four-stroke motor 45. Steps (1) and (3) denote E−Z photoisomerization, and steps (2) and (4) denote ring inversion. (b) Two-stroke motor 46. Steps (1) and (2) denote E−Z photoisomerization and thermal nitrogen pyramidal inversion, respectively. imines, enables the exploration of a wide range of possible structural modifications347 and the preparation of this class of molecular motors in large amounts. The main drawback compared to overcrowded-alkene-based motors is that while the mechanistic details of the latter have been experimentally and computationally established in detail, in the case of imine- based motors the precise stereochemical dynamics of the motion, in particular for the photochemical steps, has been mostly determined only by means of computational studies.348 Considerable experimental work still needs to be performed to fully clarify the details of the working mechanism of this fascinating new class of rotary motors. A significant step forward toward the experimental demon- stration of unidirectional rotation in chiral imine motors was reported in a follow-up study on camphor-based imines.349 In camphorquinone-derived imine 47 (Figure 45), because of the rigidity of the stator portion of the motor, the rotational mechanism was expected to operate via a two-step pathway consisting of photoinduced rotation followed by thermal inversion. Direct experimental evidence of the photoinduced unidirectional rotation, however, has proven to be extremely difficult to obtain because of the ultrafast dynamics of the excited-state reactions.350 Thus, to gain insight into the directionality of the CN bond photoisomerization, a clever experiment was designed that was based on the trapping of the two different diastereotopic biradicals formed upon excitation of fi Figure 45. Structure and mechanism of directional rotation in 47 to the S2 state with 254 nm light. Speci cally, excitation to the camphorimine-based rotary motor 47349 and structures of the trapped S2 state leads to opening of the cyclopropyl ring and formation of endo and exo photoproducts. a biradical species that can undergo CN rotation (as happens in the S1 state reached by 365 nm excitation). Before reaching ff the S1 state, some of the biradical S2 excited molecules undertake preference in the biradical species (S2 state) may di er from that  a rearrangement reaction, yielding two diastereomeric deriva- of the pure C N bond rotation (S1 state), this result is an tives (exo- and endo-trapped states) whose ratio is indicative of indirect yet convincing experimental proof of the unidirectional the preference between the two diastereotopic excited-state rotation in these chiral imines.349 trajectories that are responsible for the preferential sense of As a general message conveyed by such experimental and rotation (Figure 45). Indeed, a significant difference in the yields computational studies, it is reasonable to anticipate that all chiral of the exo and endo stereoisomers upon prolonged light imines are potentially molecular rotary motors that can be driven irradiation at 254 nm was observed. Although the rotational by light and thermal energy. This is a striking consideration if

234 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review one considers the large variety of imine intermediates that are 53 the single stereogenic center in the allylic position with formed along metabolic pathways of living cells. A most respect to the reactive double bond is sufficient to introduce interesting and still unexplored possibility is to combine the unidirectional rotation in the photoisomerization process. motional dynamics of imines with their constitutional dynamics, Moreover, the calculations revealed that even a very small which could in principle lead to dynamic libraries of motor amount of pretwist (less than 2°) or helicity in the equilibrium moieties. All of these aspects make imine-based rotary motors ground state of the reactive double bond is sufficient to promote some of the most interesting and promising molecular machines unidirectionality in the rotation, thus quantifying the minimal that chemistry has to offer. amount of “chiral information” that has to be contained in a 3.6.4. Other Systems. On the basis of the knowledge molecular motor. acquired by studying the three main classes of molecular rotary The photochemistry of simple chiral azoheteroarenes motors described in the previous sections, different research (compounds 54 and 55 in Figure 46)hasalsobeen groups have proposed or developed molecular systems able to computationally investigated, proving that in contrast to their exhibit unidirectional rotation. Most of them are the result of homoaromatic counterparts such as azobenzenes, the Z−E high-level computational studies on simple molecular systems. photoisomerization mechanisms can display a high bias toward Indeed, nowadays through accurate modeling of the shapes and unidirectional rotary dynamics.357 The proposed design is very the critical points of the ground- and excited-state potential interesting both from a theoretical perspective, as it represents energy surfaces, one can identify the presence of deactivation the first proposed rotary motor exploiting light-activated pathways of photogenerated states that lead to the unidirectional rotation around an azo double bond, and a practical perspective, rotation of a portion of a molecule with respect to another. because the photoisomerization around the NN bond is one Recently, Filatov and co-workers proposed that the well- of the best photoreactions in terms of fatigue resistance. This is known photochromic fulgides have the proper characteristics to an important characteristic for practical applications that is not 351,352 operate as molecular rotary motors under light irradiation. always taken into proper consideration in the development of Quantum-chemical calculations and molecular dynamics novel molecular motors. simulations support the hypothesis that chiral fulgide-based The only example of an experimentally realized rotary motor moieties (compounds 48 and 49 in Figure 46) are able to rotate exploiting the E−Z photoisomerization of azobenzene was reported by Haberhauer and co-workers (compound 56 in Figure 47a).358 The structure is rather complex, and the motion sequence follows a pattern of movements resembling that of motile cilia. The authors speculate that since motile cilia are exploited in nature for the transport of particles and the locomotion of cells, their motor system should in principle be able to push surrounding molecules in a definite direction during its operating cycle. The central part of the motor is a chiral macrocycle. The pyridine rings attached to the central macrocycle of the bipyridine units are forced into a fixed position during a cycle and adopt a P configuration with respect to each other. One of the bipyridine units is functionalized with an azobenzene photoswitch that is the light-driven pushing blade of the motor. The other bipyridine unit acts as a stopper and controls the direction of the movement. By alternating Figure 46. Molecular structures of different classes of computationally irradiation with visible and UV light and complexation of the investigated rotary molecular motors. The “stator” and “rotor” moieties bypiridine ring with zinc(II) and decomplexation by addition of are colored in black and red, respectively. cyclam, the phenyl group of the azobenzene unit completes a 360° rotation around a virtual axis. The whole rotation cycle consists of an alternating unidirectionally around the central carbon double bond with combination of light-induced folding and opening and rotational high quantum efficiencies and dynamics on the femtosecond movement of the azobenzene blade (Figure 47b). The time scale. The synthetic accessibility of fulgides makes this unidirectionality of the movement was supported by computa- finding interesting for applications, although the anticipated fast tional studies that evidenced the large difference in the energy dynamics of the rotational motion will likely pose a significant barriers experienced by the bipyridine blades upon clockwise or problem for its experimental validation. anticlockwise rotation of the azobenzene blade. Even though the Durbeej and co-workers carried out a computational structure of this motor is quite complex and difficult to investigation of different structures of chiral bicyclic imines generalize and its operating cycle is not autonomous, as it (50) and enamines (51), thereby finding possible novel requires four successive chemical and light stimuli in a precise 353 mechanisms to enhance the directionality of rotation and sequence, the novel and unique motional dynamics obtained proposing an elegant minimalistic design for a visible-light- makes it an interesting platform for further development. driven rotary motor constituted by a simple protonated imine 3.7. Photochemically Triggered Chemically Driven Motors conjugated to five CC double bonds (52).354,355 In an even more extreme attempt to design the simplest light- There are a few examples in the literature of molecular motors activated molecular rotary motor, the groups of Olivucci, whose activity is reversibly triggered by a light stimulus. The Leonard,́ and Gindensperger reported a computational study of fundamental difference between these and the photochemically the photoisomerization of the biomimetic indanylidene− driven motors described in the preceding sections is that in pyrrolinium framework.356 The results proved that in imine photochemically triggered motors light energy is not employed

235 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 47. (a) Structural formula and operating cycle of four-stroke molecular motor 56. (b) Schematic representation of the different motor states. The bipyridine unit bound to the azobenzene (red) pushing blade is colored light blue, and the other one is colored gray. The azo double bond is the dark-blue pivot, and the hydrogen atom that performs a 360° rotation during the operating cycle is highlighted in green. Adapted with permission from ref 358. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 48. Photoisomerization reaction of the azobenzene-derivatized ATP species 57 applied as a phototriggerable fuel for driving a kinesin molecular motor. The ATP moiety is colored in magenta, and azobenzene in the E and Z configurations is shown in blue and red, respectively. Adapted with permission from ref 359. Copyright 2012 Royal Society of Chemistry. to power the system but only to trigger the start and stop of its energy in the form of ATP into mechanical work.2,6 The force motion, which is instead powered by another source of energy. generated enables kinesin to actively transport nanoscale cargos The main advantage of using light to start the operation of a such as vesicles, chromosomes, organelles, etc. along micro- motor is related to the high spatiotemporal resolution achievable tubules. The latter are tubular polymeric protein assemblies that with a light stimulus in comparison with other types of stimuli. are about 24 nm in diameter and up to 50 μm in length and act as An efficient strategy to realize light-triggered motors that has platforms for intracellular transport and also provide structure been applied in both natural and small artificial molecular and shape to living cells.1 systems is the development of chemical fuels that can be The approach, illustrated in Figure 48, is based on 57, an ATP interconverted between an active form and an inactive form by a analogue possessing an azobenzene photochromic unit that reversible photochemical modification of their structure.257 The strongly reduces its affinity toward ATPase kinesin upon light- system developed by Tamaoki and co-workers,359 in which triggered E → Z isomerization.359 The photoisomerization of dynamic photocontrol of kinesin-driven microtubule motility is the azobenzene moiety thus acts as a switch that reversibly achieved, highlights the possibilities offered by this approach. transforms the ATP−azobenzene conjugate from a fuel to an Kinesin is an ATPase motor protein that converts chemical inert substrate for kinesin, thus enabling the reversible

236 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review photocontrol of its motile activity. The activity of kinesin motor motor unit in an ensemble, and it is a highly desirable result for protein was assessed by a gliding motility assay, a well- applications requiring controlled cargo manipulations in established and versatile technique in which the gliding motility bionanodevices and advanced soft materials. Considering the of fluorophore-labeled microtubules driven by biomolecular large number of different motor systems present in living cells, motors (typically kinesin or myosin) bound to a glass surface is the increasing knowledge of their operation mechanism, and the visualized and monitored by fluorescence microscopy. intense effort in the development of new molecular photo- Different azobenzene−ATP conjugates were developed, and switches and related techniques, this field of research has their interaction with kinesin was studied in detail to optimize significant future perspectives. the difference in affinity between the E and Z stereo- 360,361 isomers. Despite the simplicity and elegance of this 4. MOTORS WITH COMBINED PHOTO- AND REDOX strategy, only a decrease of up to 79% of the gliding velocity of ACTIVATION the microtubules, and not complete arrest, was achieved. This result was attributed to residual E isomer present at the If a molecular motor does not operate autonomously, it needs a photostationary state as a result of the incomplete E → Z sequence of (orthogonal) inputs to operate, and therefore, more conversion of the phototriggerable ATP fuel, which is sufficient than one source of energy could be used to drive a motor. If one to sustain the residual motility. of these inputs consists of a chemical reaction, accumulation of waste products, dilution effects, or interference with the motor Tamaoki and co-workers proposed another strategy to ff overcome this limitation, by developing a library of photo- molecule could a ect the long-term operation of the device. For triggered inhibitors for kinesin activity based on a family of small this reason, the design of a molecular machine that operates solely by photochemical and redox reversible reactions would in peptides functionalized with an azobenzene group (Figure fi 49).362 Extensive screening of different azobenzene−peptide principle be able to operate inde nitely as long as the correct sequence of inputs is administered to the system. To date, only one example of a molecular motor activated by light and electrons has been reported.365 Its design is partially based on the pushing motor developed by Haberhauer and co- workers, which was described in section 3.6.4.358 In compound 58 (Figure 50), two moving partsan azobenzene and a thianthreneare connected to a macrocyclic clamp that acts as a support (Figure 50). Azobenezene is the photoswitch, whose E−Z isomerization corresponds to an up-and-down movement of the motor. Thianthrene is the redox switch: upon electro- chemical oxidation, the molecular structure is converted from a bent conformation to an almost planar one; therefore, redox processes are responsible for the stretching and bending movements of the motor. The state of compound 58 is thus characterized by the E−Z configuration of the azobenzene unit Figure 49. Photoisomerization of push−pull-azobenzene-tethered and the neutral/radical state of the thianthrene moiety. The inhibitory peptides and schematization of their effect on microtubule unidirectionality of the movement is guaranteed by the chirality motility. Adapted from ref 362. Copyright 2014 American Chemical of the macrocyclic scaffold and is conditional on the trans- Society. formation of the (E)-azobenzene into only the corresponding (P)-(Z) isomer and not the (M)-(Z) one. In fact, quantum- − chemical calculations and circular dichroism (CD) measure- derivatives enabled elucidation of the structure property ments confirmed that only the (P)-(Z) isomer is present in relationships among the sequence of the peptide, the structure solution. of the linked azobenzene unit, and the inhibition activity.363 A fi The operation mechanism of motor 58 is schematized in short peptide sequence was identi ed that once linked to an Figure 50: the cycle starts from bent (E)-58 (state A). Oxidation azobenzene group in the E form displays strong inhibition affords the stretched (E)-58+ form (state B), and subsequent activity toward kinesin and is thus able to completely stop irradiation at 365 nm generates (P)-(Z)-58+ (state C). kinesin-driven gliding motility of microtubules. The inhibiting ff → Reduction leads to the formation of (P)-(Z)-58 (state D), and e ect is strongly reduced upon E Z photoisomerization of the irradiation at 405 nm resets the system to state A. In analogy azo moiety, and gliding motility with relatively high velocity is with the light-driven four-stroke motor reported by the same observed. With this strategy, the complete and reversible author,358 it is hypothesized that as the stretched planar switching of the activity of a kinesin motor protein was achieved, thianthrene can push more molecules in one direction with using UV light to activate the motion and visible light to stop it. respect to its bent neutral counterpart, compound 58 should be By introducing push−pull substituents on the azobenzene → able to push the surrounding molecules directionally when group, which increase the thermal Z E relaxation rate and shift operated cyclically. the absorption maximum into the visible range, an inhibitor moiety for controlling the gliding motion with a single visible wavelength was developed (Figure 49). With this kind of 5. FROM MOVEMENTS TO FUNCTIONS inhibitor, the translocation, bending, and breaking of a single The examples illustrated in the previous sections showcase the microtubule while the surrounding microtubules were kept at types of artificial redox- and photodriven molecular motors rest was demonstrated, showcasing the high level of spatial and available to date and highlight the level of sophistication reached temporal control affordable by such a method.364 This study is in their design, synthesis, and investigation. The time is ripe to one of the few examples of photoregulation of a selected single start developing systems in which the movement performed by

237 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 50. Structural formula and schematic representation of the molecular pushing motor 58 and its operating mechanism. Adapted with permission from ref 365. Copyright 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 51. Structural formula of compound 59 and schematic representation of the photoinduced control of the helicity of the polyisocyanate polymer chain with a covalently linked second-generation overcrowded alkene molecular rotary motor. Adapted with permission from ref 367. Copyright 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. molecular motors is not an end in itself but is exploited to controlled molecular movements in suitably designed systems accomplish a function. This is what happens in biomolecular and materials. The examples are categorized according to the motors, which utilize the motion to perform useful tasks across type of functionality enabled by the molecular movement. ff di erent length scales, encompassing molecular (e.g., the 5.1. Control of Chemical and Physical Properties making of other molecules), microscopic (e.g., intracellular transport), and macroscopic (e.g., muscle-based actuation and 5.1.1. Transfer of Chirality. The transfer of chiral locomotion) settings. information and its amplification from the molecular to the In this section we will describe experiments in which the supramolecular or macromolecular level is an interesting redox- or light-powered motion of synthetic molecular motors is research objective that can lead to applications in responsive 366 harnessed, transmitted, or collected such that a sizable change is materials, sensing, and catalysis. To this aim, molecular rotary observed beyond the motors themselves. We would like to point motors of the overcrowded alkene family (section 3.6.1) appear out that some of the systems described in the following are based to be suitable control elements because they operate according on molecular switches rather than motors or contain a molecular to a sequence of photo- and thermally induced transformations motor that is used as a switch. Nevertheless, we find it involving diastereoisomers with a well-defined helicity. A first appropriate to include them in this review because they show step forward toward dynamic intramolecular transmission of how redox- or photoinduced tasks can be achieved by harnessing chirality triggered by light is represented by compound 59

238 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 52. Photocontrol of the helicity of cationic poly(phenylacetylene)-type polymer 60 by chiral induction from molecular motor 61 bound non- covalently. Adapted with permission from ref 368. Copyright 2017 Royal Society of Chemistry.

Figure 53. Formula of compound 62 combining molecular motor and bis(bipyridine) ligand components and schematic representation of the photoinduced switching between oligomeric and monomeric double-stranded Cu(I) helicates of distinct handedness. Adapted with permission from ref 369. Copyright 2016 Springer Nature.

(Figure 51), consisting of a poly(hexylisocyanate) polymer More recently, the same concept was extended to a water- functionalized at one end with a second-generation molecular soluble poly(phenylacetylene) dynamic helical polymer bearing rotary motor moiety.367 In solution, the polymer chain assumes ammonium side groups (60; Figure 52).368 In this case the a helical conformation and is dynamically racemicthat is, the molecular motor (61) was not covalently linked to the polymer compound contains equal amounts of interconverting right- but rather intermolecularly associated with it through hydro- handed and left-handed helices. This behavior is maintained in phobic and electrostatic interactions. The chirality transfer from ff 59 when the molecular motor, appended as its S enantiomer, is 61 to 60 was investigated by CD spectroscopy; the e ects of pH, in the form of its stable (M)-(E) isomer, which exerts little salt concentration, and amount of motor dopant were studied. The results showed that the chirality of the motor can be influence on the polyisocyanate chain. Upon photoisomeriza- transferred to the non-covalently bound polymer and that the tion to the unstable (P)-(Z) form, the M-helical polymer is helical conformation of the latter can be switched by light. exclusively obtained. Successive thermal relaxation to the stable In another study, both halves of an overcrowded alkene motor (M)-(Z) isomer of the motor results in the formation of the were functionalized with oligo(bipyridine) ligand strands, which opposite helical conformation of the polymer (that is, the P are known to self-assemble into double-helicate complexes in helix). The racemic state of the polymer can be restored by the presence of Cu(I) ions (Figure 53).369 When the motor completing the motor cycle and return to the starting (M)-(E) moiety of compound 62 is in the stable (P,P)-(E) form, addition form. Therefore, the chirality transfer from the molecular motor of Cu(I) results in the formation of coordination oligomers. to the polymer dictates the preferred helical sense of the latter Photoswitching to the unstable (M,M)-(Z) isomer leads to and enables reversible switching between the racemic, M, and P disassembly of the oligomers to yield intramolecular helicates states. with defined handedness (P′). The successive thermal helix

239 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review inversion of the motor, affording the stable (P,P)-(Z) isomer, addition of 2-methoxythiophenol to 2-cyclohexen-1-one.374 The causes inversion of the chirality of the copper helicate (from P′ E isomer, wherein the functional substituents that can to M′). Further irradiation and thermal helix inversion to coordinate the substrates are far apart, exhibits low catalytic complete the rotary cycle of the motor regenerates the activity and leads to a racemic product. Upon photoisomeriza- oligomeric E state, and the switching scheme can be repeated. tion to the Z form, the two substituents become close enough to Examples of intramolecular transfer of chirality in rotary motors act cooperatively, and a significant enhancement of the reaction with tightly conformationally coupled rotors will be discussed in rate and enantioselection is observed. The chirality of the sections 5.1.2 and 5.2. Chirality transfer and amplification in product is determined by the relative helical orientation of the liquid crystals doped with overcrowded alkene molecular motors aminopyridine and thiourea substituents, which in turn depends has also been investigated (see section 5.5). on the helical configuration of the motor. Thus, the photo- 5.1.2. Catalytic Properties. In biological systems, chemical generated unstable (M,M)-(Z) isomer affords the product in the reactions are precisely controlled by means of sophisticated S configuration, while the R configuration is obtained upon catalytic mechanisms mastered by enzymes. Indeed, the making subsequent thermal relaxation to the stable (P,P)-(Z) form − of other molecules is a major task of biomolecular machinery.1 4 (Figure 54b). The last two isomerization steps of the full rotary Using synthetic molecular motors to obtain dynamic stimuli- cycle reset the catalyst to its initial state. In summary, 63 behaves responsive catalytic effects is a fascinating goal for molecular as a photochemically and thermally responsive catalyst that can machines. trigger the formation of the racemate or either of the The photoswitchable stereochemical features of overcrowded enantiomers of the product in a well-defined sequence.375 alkene molecular rotary motors were exploited to develop The system was later redesigned by removal of the phenyl catalysts for enantioselective transformations whose efficiency spacers connecting the motor to the catalytically active moieties − can be controlled by light.370 373 It was envisaged that the (64 in Figure 55).376 It was envisaged that such moieties could individual chiral forms obtained during the unidirectional rotary cycle could dictate the ability of the catalyst to induce a preferred handedness in the product of an asymmetric reaction. In an initial study, a first-generation molecular motor bearing 4- dimethylaminopyridine and thiourea units (63 in Figure 54a) was employed as an organocatalyst in the asymmetric Michael

Figure 55. Structural formulas of switchable catalysts 64−66 in their (P,P)-(E) forms.

come into closer proximity in the new catalyst, thereby forming a more constrained pocket and leading to enhanced activity and stereoselectivity. This expectation was experimentally confirmed by using 64 as a catalyst in the Henry reaction between nitromethane and trifluoroketones. Along the same line, a molecular motor was equipped with two thiourea units; the resulting compound (65 in Figure 55) also exhibited photo- switchable organocatalytic activity and stereoselectivity in an asymmetric Henry reaction.377 Compound 66 was prepared by attaching a phosphine group to each half of the motor, thus obtaining a chiral biphosphine that could function as a ligand for transition metal catalysis.378 The behavior of 66 was tested in the palladium-catalyzed Figure 54. (a) Structural formula of switchable catalyst 63 derived from a first-generation molecular rotary motor, in its (P,P)-(E) form. (b) desymmetrization of meso-cyclopent-2-en-1,4-diol bis- Schematic representation of the photochemical and thermal control of (carbamate), a well-known model reaction to study the the activity and enantioselectivity of 63 in the Michael addition of 2- enantioselectivity of chiral ligands. When the (P,P)-(E) isomer methoxythiophenol to 2-cyclohexen-1-one.374 Adapted with permis- was used as the ligand for Pd, a nearly racemic product sion from ref 54. Copyright 2017 Springer Nature. (enantiomeric ratio 53:47) was obtained in 65% yield. Upon

240 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review photoisomerization to the (M,M)-(Z) isomer, the palladium It should be pointed out that all of the systems described complex of 66 was shown to catalyze the reaction in 90% yield above, as well as several examples presented in the next sections, with an enantiomeric ratio of 93:7 in favor of the (3R,4S)- do not harness the photoinduced directional, repetitive, and oxazolidinone product. Conversely, after isomerization to the autonomous rotary movement characteristic of the motor, (P,P)-(Z) isomer, the opposite enantiomer, (3S,4R), was which is therefore used as a light-responsive switch. Molecular obtained with an enantiomeric ratio of 6:94 in 85% yield. rotary motors, however, offer a higher degree of control with Unfortunately, the palladium catalyst could not be switched in respect to conventional bistable photochromic compounds situ because of the poor stability of the species generated by UV because they act as multistate switches in which the various irradiation and heating, which leads to a decrease in selectivity. states exhibit different structures (e.g., size, shape, helicity) and In a more recent work, a second-generation molecular rotary features (e.g., polarity, optical properties). motor was combined with a 2,2′-biphenol unit to yield 5.1.3. Biological Functions. Stimuli-induced change of compound 67 (Figure 56).379 The biphenol moiety was selected structural features is a powerful means to regulate the functions of biomolecules. In the attempt to develop biohybrid systems that can exhibit similar behavior, molecular machines are promising candidates to play the role of mechanical control elements. A first step along this direction is the recently reported functionalization of a DNA hairpin with a first-generation motor of the overcrowded alkene family.380 The motor, whose halves were functionalized with rigid connectors to render it a bifunctional linker, was incorporated into a 16-mer strand of self-complementary DNA via solid-phase synthesis. The results showed that the presence of the motor as a bridgehead does not hamper the formation of the eight-base-pair hairpin and that the photoisomerization and thermal helix inversion steps at the basis of the motor function are retained in the hairpin. The E/Z configuration of the motor was found to affect the stability of the fl ff duplex, as re ected in di erent melting temperatures (Tm) of the E and Z hairpins. Contrary to what expected from the design of the system, aided by DFT calculations, the E hairpin is more Figure 56. Design strategy, structural formula, and photoinduced stable than the Z one. UV irradiation experiments performed switching of compound 67. Acting as a catalyst in an enantioselective over a temperature range around the melting temperature of the addition, this compound features point-to-helical-to-axial-to-point hybrids indicated that the duplex stability of the oligonucleotide transfer of chirality. Reproduced from ref 379. Copyright 2018 can be adjusted by light stimulation. The overcrowded alkene American Chemical Society. switch exhibits a number of advantagessuch as efficiency, structural rigidity, multistate behavior, and helicity inversion over azobenzene species used in earlier studies of photo- because of its ability to function as a bidentate ligand for a metal controlled DNA hybridization,381 highlighting the potential of center, thus forming a complex with potential catalytic activity. molecular rotary motors to engineer photoregulated processes Because of the tight steric coupling of the motor and biphenol in biological systems. moieties, it was envisaged that the preferred axial chirality of the Overcrowded alkene rotary motors bearing either dye units biaryl (highlighted in green in Figure 56) would be dictated by (cyanine for 68, boron dipyrromethene (BODIPY) for 69; the helicity of the overcrowded alkene core (blue), which in turn Figure 57) or oligopeptide chains (in the case of 70−73) on the is determined by the configuration of the stereogenic carbon stator were physisorbed on either synthetic lipid bilayers or cell atom (red). The photoswitching properties of 67 and the related membranes, and the effect of photochemical irradiation on the stereochemical changes were studied by detailed NMR, UV, and membrane stability was assessed.382 Remarkably, the presence CD spectroscopy experiments. The results showed that light of the dyes in 68 and 69 does not quench the photoreactivity of ff 383 irradiation a ords reversible switching between the (R,P,Sa) and the motor core. Molecular motors with smaller substituents (R,M,Ra) stereoisomers, indicating that changing the helicity of (74 and 75) were also considered, as well as a number of control the motor changes the chirality of the biphenol. The behavior of compounds. The latter include 76, a switch that can undergo 67 as a catalyst was tested in an asymmetric addition reaction of only E−Z photoisomerization without a full rotation, i.e., it can diethylzinc to aromatic aldehydes. The active catalyst is formed only exhibit a flapping (reciprocating) motion; 77, a molecule upon coordination of 67 to a zinc ion through the biphenol derived from 74 but lacking the allylic methyl group, which ligand. Interestingly, reversal of the enantioselectivity upon exhibits light-induced random (not unidirectional) rotation; 78, photoirradiation was observed for several substrates, suggesting a stator with no rotor; and 79, a photochemically inactive that the metastable (R,M,Ra) isomer of the catalyst resembles chromophore mimicking the absorption properties of the fi the enantiomer of the stable (R,P,Sa) isomer as far as the chiral motors. In a rst series of experiments, compound 68 and a induction is concerned. This study demonstrates that switchable BODIPY dye were coencapsulated into large unilamellar vesicles chiral catalysts can be obtained by the designed integration of (LUVs) self-assembled from phospholipids. Upon irradiation of functional elements with well-defined stereochemical proper- the LUV suspension at 365 nm, a decrease in the BODIPY-based ties. The tight conformational coupling at the basis of the luminescence intensity of the vesicles was detected by confocal transmission of chiral information from the motor to the catalyst fluorescence microscopy. Control experiments confirmed that is reminiscent of the function of a mechanical geara concept such a decrease can be attributed to the destabilization of the that will be illustrated in more detail in section 5.2. membrane caused by the photoactivated motion of 68 within

241 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 57. Structural formulas of molecular rotary motors 68−75 and control compounds 76−79 used in investigations of the photodestabilization of bilayer membranes.382 the bilayer, thus enabling the escape of BODIPY dye molecules. in compounds 70−73, allowed the targeting of specific cells. This kind of phenomenon, although interesting, is not Little or no cell death was observed upon UV irradiation in − unprecedented for molecular photoswitches;384 386 moreover, control experiments performed with compounds 76−79, a connection between the membrane perturbation and the suggesting that the nonreciprocating unidirectional rotation of unidirectional rotation of the motor was not clearly established. the molecular motors is crucial to afford their efficient light- Successively, compounds 68 and 69 were introduced into induced penetration through the lipid bilayer. It is hypothesized living cells, and their behavior with and without UV irradiation that membrane rupture and pore formation are induced by a was studied in vitro by optical microscopy.382 The observations tangential mechanical force exerted by the rotating nanomotors showed that the cell internalization of these species is embedded in the bilayer (Figure 58). The disruption of external significantly accelerated upon light irradiation to cause rotation or internal cellular membranes can be used to introduce species of the molecular motors. The same experiments performed with into cells or to expedite cell death. Appropriate functionalization motors 74 and 75 indicated a photoinduced perturbation of the of the motors enables fluorescence tracking of the molecular cell membrane, resulting in membrane blebbing and necrosis. motors within cells or targeting of specific cells by exploiting The addition of peptide substituents to the molecular motors, as surface recognition elements. All of these features offer

242 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

opportunities for the application of molecular motors to solve biomedical problems. 5.2. Transmission of Directed Motion within Molecular Systems In macroscopic mechanical machines, the movement produced by a motor componentthat is, an active device that uses an energy source to generate forcesis transmitted and processed by means of other passive elementse.g., gears, belts, and jointsthat are mechanically coupled to the motor. Biological systems show that the mechanical coupling of molecular motors with other molecular components of the surrounding environ- ment is essential also for molecular machinery performing − Figure 58. (a) Schematic representation of molecular motors tasks.1 4 physisorbed on a cell membrane. (b) UV-induced rotation of the Concerted movements were observed in ingeniously designed motors induces membrane rupture and pore formation. Reproduced synthetic molecules consisting of sterically coupled moieties, with permission from ref 382. Copyright 2017 Springer Nature. leading to nanoscale versions of mechanical devices24,27,62,63,387 such as cogwheels,388,389 bevel gears390,391 and drive chains392

Figure 59. Mechanical coupling of molecular components: (a) cogwheels,389 (b) bevel gear,391 and (c) drive chain.392 These molecular devices are based on passive rotors and thus exhibit random nondirectional motion driven by thermal energy.

243 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 60. Structural formula of compound 80 and schematic representation of its four-stage photochemical and thermal switching cycle that affords the transfer of a directionally controlled rotary movement from the motor to the rotor.393 Upon unidirectional rotation of the overcrowded alkene core (blue rotor and gray stator), the appended naphthyl paddle (red) revolves around the motor axis (orange) and rotates around the rotor axis (green). The different faces of the naphthyl paddle are marked to highlight the tidal locking.

Figure 61. Structural formula of macrocycle 81 and representation of the photochemically and thermally driven steps at the basis of the transmission of directional rotation from the hemithioindigo motor (blue rotor and gray stator) to an aryl paddle (red) by means of an ethylene glycol linker (purple).394 The rotation axes of the motor and the passive rotor are colored in orange and green, respectively.

(Figure 59). These movements, however, have a Brownian Feringa and co-workers recently reported the first example of origin and therefore lack the directionality necessary to perform synchronous transmission of photoactivated directional motion stimuli-induced functions. from a second-generation overcrowded alkene motor to a

244 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 62. (a) Structural formula of [1]rotaxane 82 and (b) schematic representation of its photoinduced switching that converts the flapping motion of the stilbenoid unit into linear translation of the pillararene ring along the axle.396

Figure 63. (a) Structural formula and cartoon representation of [1]rotaxane 83 comprising a photochemically driven molecular rotary motor. As shown in (b−e), the light-driven rotation of the motor results in concomitant translation of the ring with respect to the axle. Adapted from ref 397. Copyright 2019 American Chemical Society. coupled rotor.393 Compound 80 (Figure 60) consists of a and synchronized, as happens for the tidally locked movement of naphthyl rotor covalently appended to the indanyl half of the the Moon around the Earth. The precision in the transmission of rotary motor, such that the motion of the rotor is locked with the the motion relies on an appropriate tuning of the energy barriers light-triggered rotation of the motor. NMR and CD spectros- associated with the different rotary movements, which was copies were employed to identify unambiguously all of the obtained by clever molecular design. structures involved in the operating cycle and to study the An alternative approach for the intramolecular transmission of kinetics of the transitions between them. The results unidirectional rotary motion from a molecular motor to a demonstrated that during a full rotation of the motor, the passive rotor was recently reported by Dube and co-workers.394 naphthyl paddle slides along and rotates around the fluorenyl Compound 81 (Figure 61) consists of a biaryl unit, acting as the unit of the core, always facing it with the same side (Figure 60). passive rotor, incorporated within the stator half of a light-driven Thus, the rotations around the rotor and motor axes are locked hemithioindigo motor (section 3.6.2). In this macrocyclic

245 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review species, an ethylene glycol chain links the rotor half of the motor and transfer it to the methyltriazolium (MT) site (Figure 63b). with the aryl paddle of the passive rotor in an off-axis manner Upon UV irradiation, the motor begins its rotation cycle, which with respect to the biaryl rotation axis. It was envisaged that the causes the ring to dissociate from the MT unit of the axle and ethylene glycol tether could transfer the photochemically driven slide along the hydrocarbon chain (Figure 63c). The thermal unidirectional rotation of the motor to the remote biaryl rotor by helix inversion of the motor affords the stable E form (Figure exploiting the steric strain created in the different stereoisomers 63d). The successive absorption of another UV photon drives involved in the operating cycle of the device. The behavior of 81 the second half-turn of the motor, which pushes the ring back to was investigated by CD and NMR spectroscopies together with the MT site (Figure 63e); a final helix inversion affords the stable quantum-chemical calculations and crystallographic analyses. Z form of the motor, thus completing the cycle. Apart from the Like 80 and the related compound 67 discussed in section transmission of movement (it should be noted, though, that the 5.1.2, compound 81 contains three stereogenic elements, unidirectional rotation is transformed into a reciprocating namely, point chirality around the sulfoxide unit, helicity around shuttling motion), this study is interesting because it highlights the motor double bond, and axial chirality around the biaryl axis. that the molecular rotary motor can function against the non- The starting state of the device is the (R,M,Sa/Ra)-(E) isomer, in covalent interactions that occur between the DB24C8 ring and fl which the exible ethylene glycol chain allows the interconver- the MT site. sion between the R and S atropisomers in dichloromethane a a 5.3. Locomotion at the Nanoscale solution at room temperature (Figure 61a). Irradiation of this ff species at 470 nm a ords the (R,M,Ra)-(Z) stereoisomer 5.3.1. Molecular Swimmers. Some kinds of bacteria (e.g., (Figure 61c), whose CD spectrum is consistent with the biaryl Escherichia coli) use the biomolecular motor-powered rotation8 fi fl unit occurring in the Ra con guration. Indirect evidence suggests of a lashlike appendage (the agellum) protruding from the cell that this transformation takes place through the formation of the body to move across a fluid medium.3,4 Achieving the propulsion unstable (R,P,Sa)-(Z) intermediate (Figure 61b); although this of a micro- or nanoscale object is a major challenge because at isomer could not be experimentally observed, only minimum- these length scales inertial forces, which are at the basis of energy structures in which the biaryl unit is in the Sa swimming at the macroscopic scale, are absent, and motion is configuration were found in a computational analysis. Successive dominated by the viscosity of the medium.64,96,97 The ratio of irradiation of the (R,M,Ra)-(Z) stereoisomer with 470 nm light the inertial and viscous forces for a given object can be expressed ff a ords the (R,P,Ra)-(E) form (Figure 61d), which successively by a dimensionless parameter, the Reynolds number (Re). A undergoes thermal relaxation to the starting state. Thus, the large Re indicates that inertia dominates, whereas very low values biaryl rotor of 81 experiences a spatially restricted rotational of Re could be due to the small dimension of the object and/or freedom because of the covalent constraints, and its config- high viscosity and indicate that motion is governed by viscous uration reflects that of the motor core; as a result, the light- forces. It is easy to show that the extremely small size of driven unidirectional rotation of the hemithioindigo moiety is nanoscale objects results in very low Reynold numbers. In such a transferred to the passive rotor. regime, propulsion based on conventional swimming mecha- An important feature of the systems described above, in nisms, which rely on time-reversible strategies (Figure 64a), is comparison with the previously reported transfer of controlled impossible; any net displacement must involve a nonreciprocat- fi 395 movements within arti cial molecular machines, is that the ing motion to break the time-reversal symmetry (Figure rotation generated by the motor is autonomous and unidirec- 64b,c).399,400 Another significant issue is represented by tional and that such extremely valuable properties are preserved 387 Brownian motion (i.e., thermally driven collisions with solvent upon transmission. molecules), which tends to randomize the trajectory of small Attempts to couple rotary and translational movements have also been reported. Yang and co-workers synthesized compound 82 consisting of a [1]rotaxane in which the axle and ring components are linked by means of an overcrowded alkene (or “stiff stilbene”) moiety (Figure 62a).396 The stilbenoid unit can undergo E−Z photoisomerization, but it does not exhibit unidirectional rotation. As shown schematically in Figure 62b, the change in the distance between the two aromatic halves of the switch, caused by their relative rotation, results in linear movement of the pillararene macrocycle along the axle. Although this system contains no molecular motors (both movements are reciprocating), it represents an interesting example of combining rotary and linear mechanical devices. Very recently, along the same idea, a second-generation Figure 64. (a) “Scalloplike” motion, which relies on reciprocating overcrowded alkene rotary motor was covalently combined with flapping of two halves connected by a hinge, is ineffective at very low a rotaxane-based molecular shuttle architecture397 according to Reynolds numbers. Because of the high viscosity of the medium, any a design previously exploited to achieve chemical gating of a directional displacement achieved in the first half-cycle would be 398 canceled by the opposite displacement caused by the second half-cycle. photochemically driven molecular rotary motor. In com- fl fi pound 83 (Figure 63a), the rotor and stator moieties of the (b) In the exible oar mechanism, the oar bends one way during the rst half-cycle and the other way during the second half, thus avoiding time- molecular motor are functionalized with a DB24C8-type ring reversal symmetry. (c) The corkscrew mechanism exploits the coupling and an ammonium-containing axle, respectively, which are in of rotational and translational motion around the axis of a helicoidal turn interlocked together to yield a [1]rotaxane. The working filament. Mechanisms (b) and (c) are both employed in bacterial cycle begins with deprotonation of 83 to “unlock” the crown swimming. Adapted from ref 399, with the permission of the American ether from the ammonium center (which has become an amine) Association of Physics Teachers.

246 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 65. (a) Structural formula of nanocar 84 incorporating a light-powered molecular rotary motor in its chassis.404 (b) Schematization of the proposed propulsion mechanism: irradiation with 365 nm light, together with thermal activation, operates the motor (green stator and blue rotor), whose unidirectional rotation causes the forward movement of the nanocar relative to the surface. moving particles and hampers imparting directionality to their motor into the chassis of a carborane-wheeled vehicle (84 in displacement. Figure 65a).404 The use of only one motor per vehicle removes The unidirectional (nonreciprocating) rotation of a molecular the need for chiral resolution in the synthesis because a given motor could in principal be exploited to achieve propulsion. A motor can only rotate in a specific direction. It was envisaged crucial problem in this regard is performing the motion that the unidirectional rotation of the motor could cause repetitively with a frequency high enough to produce observable directed translational motion on the surface according to a effects against random Brownian motion. Molecular rotary paddlewheel-like mechanism (Figure 65b). While single motors of the overcrowded alkene family, because of their ability molecules of 84 could be deposited and imaged on a copper to carry out fast and autonomous unidirectional rotation cycles, surface, no lateral motion was observed upon light irradiation or seem to be a suitable choice. An attempt along this direction was STM manipulation, presumably because of strong molecule− reported by Tour and co-workers, who investigated the solution surface interactions.405 behavior of compound 68 (Figure 57) and other related model More recently, the photoinduced displacement of a motorized compounds by fluorescence correlation spectroscopy.383 As nanovehicle on a metal surface was described.406 Compound 85 discussed in section 5.1.3, 68 comprises a photochemically (Figure 66a) looks like a roadster and consists of a second- driven molecular motor and a cyanine fluorophore that can be generation overcrowded alkene motor attached to a phenylene optically tracked. The results showed that UV irradiation of 68 ethynylene axle terminated with two adamantane wheels. The causes an increase of the apparent diffusion coefficient by 26% in molecules were deposited on an atomically flat Cu111 surface acetonitrile. Model compounds analogous to 68 but bearing under ultrahigh vacuum, and an STM was used to follow the either a slowly rotating motor or a stator with no rotor (akin to motion of individual objects. The influence of light on the 76 and 78, respectively, in Figure 57) do not exhibit any UV- behavior of surface-deposited 85 was assessed by (i) imaging induced increase in diffusivity. However, a molecule related to individual molecules in their initial positions, (ii) retracting the 68 equipped with a non-unidirectional photoswitch in the place STM tip to allow in situ illumination of the sample, and (iii) of the motor (akin to compound 77 in Figure 57) also showed approaching the STM tip again to image the same surface area an enhanced diffusion coefficient under light irradiation. and determine the molecular positions after illumination. As Thermal effects associated with light irradiation were ruled out thermal helix inversion steps are necessary for the rotation of the by experiments; nevertheless, the mechanism at the basis of the motor, the effect of temperature was also investigated. photoinduced enhancement of diffusion remains unclear. At temperatures above ∼150 K, the molecules begin to diffuse 5.3.2. Surface-Roving Nanovehicles. One of the most across the surface (Figure 66b). STM imaging combined with in imaginative applications of artificial molecular motors is situ illumination performed at 161 K revealed that the certainly as engine components in nanometer-sized vehicles nanoroadsters can diffuse for rather long distances upon that can move directionally and autonomously across a surface. irradiation with light of a wavelength absorbed by the motor Nanovehicles consisting of rotating molecular wheels connected (Figure 66c,d). Analysis of the individual behaviors of a to a rigid molecular chassis have been synthesized and statistically significant group of molecules not only confirmed − investigated.116 119 The first prototypes, developed by Tour this observation but also indicated that the enhancement of the and co-workers, were devoid of a motor and thus not capable of diffusion steps was larger for 355 nm light (Figure 66d), which is controllable autonomous movement.401,402 These nanovehicles, closer to the absorption maximum of the motor, than for 266 nm however, could be deposited on a metal surface and pulled/ light (Figure 66c). Irradiation at a wavelength not absorbed by pushed using the tip of a scanning probe microscope.403 Later, the motor (635 nm) caused only a very minor effect, and with the objective of constructing a motorized nanocar, the same illumination experiments performed on a motorless control group incorporated an overcrowded alkene molecular rotary compound resulted in no diffusion enhancement. Taken

247 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

viewed here because their operation does not rely on redox or photochemical excitation. 5.4. Controlled Transport of Molecular Cargos A crucial task performed by biomolecular machines is controlled − directional transport of substrates within cells.1 6 In fact, ions and small molecules can diffuse to where they are needed, but larger entities such as vesicles and organelles would move too slowly across the cytosol and need to be transported by motor proteins. These machines comprise a motor domain, which is capable of moving directionally along a track by consuming ATP, and a docking domain, to which appropriate cargos may be attached and detached on demand.5,6 The design and construction of artificial molecular machines that can actively transport molecular or ionic substrates along specific directions or across membranes is a fascinating goal for nanoscientists and may disclose unconventional routes in catalysis, smart materials, − energy conversion and storage, and medical therapy.410 413 While outstanding examples of molecular robots414 capable of transporting and sorting cargos have been developed by − engineering of DNA architectures,415 419 the development of fully synthetic systems is still in its infancy.420 5.4.1. Systems Based on Linear Molecular Switches. Figure 66. (a) Structural formula of motorized nanoroadster 85.(b−d) Multicomponent rotaxane 86 (Figure 67a) was designed to Difference images obtained from STM experiments at 161 K showing achieve the controlled capture, transport, and release of the roadsters at their starting position (dark) and after (white) either ff ruthenium(II) polypyridine complex 87 under chemical and thermally induced di usion (b), irradiation at 266 nm (c), or irradiation photochemical stimulation.421 The rotaxane is composed of a at 355 nm (d). The red circles in (c) and (d) highlight a molecule that dibenzo[24]crown-8-type macrocycle and a molecular axle that underwent a long-distance displacement. Scale bars, 20 nm. Adapted ′ from ref 406. Copyright 2016 American Chemical Society. contains a dibenzylammonium site (primary station) and a 4,4 - together, these results indicate that a light-driven process due to the presence of the molecular motor enables long-distance translation steps across the surface. However, the observations are not sufficient to confirm that a paddlewheel-like mechanism such as that shown in Figure 65b is at the basis of the motion. It could happen that the stereoisomers of the motor populated by light irradiation exhibit different diffusion properties, possibly because of changes in the molecule−surface interaction, thus resulting in a photoinduced increase in the observed diffusion. A similar behavior was recently observed for photoactive azobenzene tetrapods adsorbed on a silver surface.407 It is worth pointing out the crucial role played by temperature in these experiments. In studies carried out at 6 K, the nanoroadsters did not move, whereas at temperatures above 170 K, thermally driven diffusion became faster than STM imaging. At low temperatures it can be presumed that the thermal energy is not sufficient to enable the thermal helix inversion of the motor; conversely, if the temperature of the surface is too high, then random Brownian diffusion dominates the motion. Nanocars derived from 84 (Figure 65) were equipped with BODIPY fluorescent dyes to allow tracking of the movements of individual molecules by fluorescence microscopy.408 Scanning tunneling microscopy outperforms single-molecule fluorescence microscopy in terms of imaging resolution, but the latter technique does not require the use of conductive surfaces and ultrahigh-vacuum conditions. Indeed, individual fluorescent nanocars lacking the motor component were successfully fl 409 located and tracked by uorescence microscopy. Figure 67. (a) Structural formulas of rotaxane transporter 86 and cargo As mentioned in section 1.3.2, examples of surface-mounted 87. (b) Schematic representation of the transport cycle. The cargo single-molecule motors activated by means of the tunneling loading/unloading is performed by a thermally reversible photoinduced 113−119,405 current provided locally by the STM tip including ligand dissociation, while the ring transfer/return is achieved by Feringa’s famous four-wheel-drive nanocar116are not re- addition of basic and acidic reactants.421

248 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 68. Reversible intramolecular transport of a cargo (red) between two distant chemically equivalent sites (blue and green) in compound 88 containing a hydrazone-based rotary switch (purple).426 TCEP = tris(2-carboxyethyl)phosphine. bipyridinium unit (secondary station). In this kind of cargo rely on orthogonal switching processes and can be compound, the ring selectively encircles the ammonium site; controlled by noninterfering stimuli. Furthermore, the use of a deprotonation of the latter with a base causes transfer of the kinetically inert coordination bond ensures that the cargo macrocycle to the bipyridinium station. The initial situation is remains docked to the machine during ring shuttling. These are restored by adding an acid to regenerate the ammonium site. both essential requirements to carry out the transport Therefore, the movement of the ring in 86 can be controlled correctly.421 It should also be pointed out that the time-reversal reversibly by chemical acid−base stimulation.422 The macro- symmetry of ring shuttling between the two stations is broken by cycle is functionalized with a short chain ending with a nitrile the (stimuli-controlled) presence or absence of the cargo. group that serves as an anchoring point for the cargo. Hence, the sequential operation of the two distinct molecular Specifically, the latter is a [Ru(tpy)(bpy)L]2+ complex in switches can lead to the net performance of a task. In the present which tpy and bpy are chelating ligands (tpy = 2,2′;6′,2″- case the transport is unproductive because the cargo is captured terpyridine; bpy = 2,2′-bipyridine) and L is a monodentate and released in the same homogeneous solution; appropriately ancillary ligand (e.g., an acetonitrile solvent molecule). Under designed rotaxanes, however, could be embedded in membranes appropriate conditions, in a solution containing 86 and 87, the and used to shuttle cargos across physically separated compart- monodentate ligand of the ruthenium complex can be replaced ments. A passive molecular transporter of this kind, which by the nitrile terminus of 86, leading to coordination of the cargo transports K+ ions across a membrane down a concentration to the transporter, whose ring is initially located on the gradient, has recently been described.195,425 ammonium station (Figure 67b). Addition of a base causes the 5.4.2. Systems Based on Rotary Molecular Switches. transfer of the ring toward the bipyridinium station and does not Intramolecular transport of a molecular cargo between two affect the cargo, which thus remains attached to the ring. At this distinct sites at the extremities of a molecular platform has been point, irradiation with visible light induces the decoordination of realized in prototypical devices. They use molecular rotary the Ru(II) complex from the nitrile tether of the rotax- switches to move a robotic “arm” in such a way that its distances ane;281,423,424 this reaction has no effect on the position of the from the different extremities of the platform can be changed in ring. Upon successive addition of acid, the (unloaded) ring response to external stimuli. Another orthogonal stimulus is returns to its initial position, and in principle the cycle can be employed to control the docking of the cargo at the robotic arm repeated; in practice, thermal recoordination of the rotaxane to and at either site on the platform, enabling controllable transport the cargo was not observed in situ, presumably because the in either direction. The cargo never detaches from the machine, vacant coordination position at the ruthenium center is thus preventing the exchange with other molecules in the occupied by a ligand (e.g., an anion or an adventitious water solution. molecule) stronger than the −CN moiety of 86. The first example, reported by Leigh and co-workers,426 It is worth noting that in this device the translocation of the consists of a hydrazone rotary switch427 whose “stator” is macrocycle between the stations and the capture/release of the functionalized at either end with two chemically equivalent (but

249 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 69. Structural formulas of molecular transporter 89 and its protected precursor 90 and operating scheme underlying the chemically and photochemically triggered transport of an acetyl cargo (red) from a phenoxy “departure” site (blue) to a benzylamine “arrival” site (green).428 The light-driven motor unit used as the rotary switch is colored in purple. experimentally distinguishable) docking stations for a 3- first-generation motor endowed with three distinct appendages: mercaptopropionyl hydrazide cargo while the “rotor” is (i) a phenoxy moiety on one side of the stator, to which the terminated with a thiol unit (88 in Figure 68). The distance cargo is initially bound; (ii) a benzylamine moiety on the other between the two extremities of the rigid platform is side of the stator, where the cargo may be delivered after approximately 2 nm. The redox-triggered reversible formation rotation; and (iii) a thiol-terminated arm in the rotor that can of disulfide bonds controls the capture and release of the cargo grip the cargo. The operation (Figure 69) begins with acid- from the rotor “arm”, whereas acid−base-sensitive dynamic catalyzed cleavage of the trityl and Boc groups that protect the hydrazone bonds are employed to control the docking to the thiol and amine moieties, respectively, in precursor 90 (Figure platform. Acid−base stimuli also mediate the operation of the 69), followed by treatment with a base. The cargo is picked up by rotary switch.427 As shown schematically in Figure 68, the cargo the rotor arm via the reaction of the thiolate moiety with the is initially mounted on the left-hand side of the platform. The phenolic ester to form a thioacetate. Subsequent irradiation at sequential addition of CF3COOH and I2 as an oxidant results in 312 nm causes rotation around the CC axis, bringing the the formation of a disulfide bond between the arm and the cargo. thioacetate close to the benzylamine unit. Acetyl transfer to the Successive treatment with a large excess of CF3COOH followed amine then occurs, transferring the cargo from the rotor arm to by an excess of Et3N leads to release of the cargo from the left- the stator. The net result of this series of reactions is the hand site and its repositioning on the right-hand site. Finally, intramolecular transport of the acetyl cargo from one extremity cleavage of the disulfide bond by reduction with tris(2- of the stator to the other, covering a distance of about 2 nm. carboxyethyl)phosphine (TCEP) detaches the cargo from the 5.5. Amplification of Motion by Collective Strategies arm, and the left-to-right transport is accomplished in 79% yield. Backward transport of the cargo can also be obtained with an In skeletal muscles, the forces exerted by single myosin ffi fi −12 overall e ciency of 85% by I2-promoted disul de formation, molecules (ca. 10 N) are collected over a huge number of acid-catalyzed rotation of the hydrazone switch, neutralization individuals and summed up, such that macroscopic forces can be with trimethylamine, and reduction of the disulfide with TCEP. eventually generated.2 Such a tremendous amplification effect is A similar design scheme was later applied to develop an artificial achieved by means of a precise, multistage hierarchical molecular assembler that can be programmed to make any one organization that, starting from the molecular scale, involves of four stereoisomers of the product using a given set of increasingly larger and complex structures. The smallest reactants.420 This remarkable nanodevice is not described here functional element of the muscle is the sarcomere, in which because although it involves reductive bond cleavage, it does not filaments made of many myosin molecules are interdigitated make use of redox stimulation. with actin filaments. The ATP-fueled gliding of these filaments More recently, Feringa and co-workers used an overcrowded with respect to one another causes contraction of the sarcomere. alkene rotary motor to construct a device operated by light that Many thousands of sarcomeres are connected in series to yield can transfer an acetyl group between distant sites within the myofibrils, which in turn are aggregated into fascicles and thicker molecule.428 The activated transporter (89 in Figure 69)isa fibers. Thanks to this stunning organization, the motion of

250 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review individual molecular motors can be accumulated in space and determines a clockwise rotation of the typical “fingerprint” time, leading to macroscopic actuation. cholesteric texture, which can be visualized with the aid of a In the past few years, amplification of motion from the microscopic glass rod lying on the surface. Indeed, irradiation molecular scale to the microscopic170,429,430 and macro- with 365 nm light triggered the clockwise rotation of the rod, scopic73,431,432 scales has been obtained in proof-of-principle which could be imaged with an optical microscope (Figure studies in which carefully designed mechanical molecular 70b−e). The motion gradually stopped after a few minutes, − switches are deposited on surfaces,433 437 incorporated into when a photostationary distribution of the motor isomers was − polymeric materials436,438 441 or arranged in crystalline reached. When the irradiation was turned off, reverse rotation − structures.442 444 In this section we discuss recent investigations was observed as the initial isomer distribution was restored. The aimed at collecting the action of many artificial molecular use of the other enantiomer of the motor caused the rod to rotate motors in organized assemblies in order to achieve effects at in the opposite direction. It is worth noting that the rotation of larger length scales. the rod is not the result of the unidirectional rotation of the 5.5.1. Doped Liquid Crystals. As discussed in section 5.1.1, molecular motor molecules but rather a consequence of their the chirality present in small-molecule rotary motors of the switched helicity. Nevertheless, the amplification of the overcrowded alkene family can be scaled up to the macro- movement from the molecular world to a scale on which an molecular level. Another way to transfer and amplify structural object could be seen to rotate was a landmark accomplishment information from individual molecules to extended supra- in the field of molecular machines. molecular assemblies is to exploit liquid crystal (LC) phases.445 The photoinduced change in the helical organization of Feringa and co-workers showed that doping a nematic LC with cholesteric LC phases induced by molecular rotary motor enantiopure second-generation molecular motors such as 91 dopants was exploited by Yang, Yang, and co-workers to (Figure 70a) induces the formation of a cholesteric phase in construct diffraction gratings that could be configured by light irradiation and erased thermally.448 These devices are based on a cholesteric liquid crystal doped with enantiopure molecular motor 92 (Figure 71a); the planar texture of the LC is stabilized

Figure 71. (a) Structural formula of compound 92 used as a dopant in cholesteric liquid crystals. (b) Scheme of the photoinduced and thermoreversible transition between the planar alignment and focal conic state of the LC helical superstructures. (c) Construction of a diffraction grating by the photoinduced local transition from the planar Figure 70. (a) Structural formula of molecular motor dopant 91.(b−e) state to the focal conic state obtained by UV irradiation through a mask. Optical micrographs of a microscopic glass rod lying on a liquid- Stabilizing polymer molecules are shown in green. (d) Polarized optical crystalline thin film doped with 1% w/w 91: (b) starting state (before micrographs of a polymer-stabilized LC film as-prepared (left), after irradiation); clockwise rotation of the glass rod by (c) 28° after 15 s of UV irradiation for 40 s (center), and after successive relaxation in the irradiation, (d) 141° after 30 s, and (e) 226° after 45 s. The scale bar is dark at room temperature for 1350 s (right). Adapted from ref 448. 50 μm. Adapted with permission from ref 446. Copyright 2006 Springer Nature. by in situ photopolymerization. The UV-induced twist of the cholesteric helix arising from isomerization of the molecular which the helical pitch of the cholesteric LC is determined by the motor is accompanied by disruption of the planar alignment in helicity of the motor units.446,447 As every step in the rotary favor of a focal conic state characterized by strong light process of the motor is accompanied by a change in helicity, scattering (Figure 71b). By performing the UV irradiation irradiation of the dopant in the sample causes a reorganization of through a mask (Figure 71c), diffraction gratings consisting of the liquid crystal. When a thin film of this LC is placed on top of alternating lines of planar alignment and focal conic structures an aligned polyimide layer, the photoinduced rearrangement could be constructed (Figure 71d). The gratings showed a

251 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review diffraction efficiency of up to 35% and were erased within minutes at room temperature because of the thermal reset of the motor dopant. Katsonis, Lacaze, de Pablo, and collaborators studied the light-responsive behavior of cholesteric LC droplets doped with alkene molecular motors.449 Such droplets exhibit peculiar topological features, such as microcavities, determined by the ratio between the cholesteric pitch and the droplet radius. Experiments performed on a large number of micrometer-sized droplets, together with simulations, revealed that the photo- induced change of the cholesteric pitch driven by switching of the helicity of the molecular motor dopant can be used to control the position of topological defects and the handedness of the radial spherical structure of the droplet. These results are thought to be of interest for optoelectronic applications involving the processing of polarized light.450 In the examples described above, the light-triggered LC rearrangement ceases as soon as the concentrations of the isomeric forms of the molecular motor reach a photostationary state. In general, this limitation can be circumvented by Figure 72. (a) Polarized optical micrographs showing axially symmetric modulating the irradiation conditions in time and space at the chiral patterns with opposite handedness (highlighted by the dashed macroscopic scale in order to obtain an oscillating behav- 71,72,75,76,78,80−85,87,88,451 twisted crosses) observed when a liquid crystal doped with an ior. An LC-based system was recently enantiopure molecular rotary motor and a chiral codopant is embedded reported in which the emergence of oscillations under within two closely spaced glass slides and irradiated with low-intensity photostationary conditions results from molecular-level behav- 375 nm light. No rotation of the patterns is observed. (b) Upon 452 ior. The liquid crystal, doped with overcrowded alkene increasing the irradiation power (P) above a certain threshold (Pthr), molecular rotary motors and with a bridged 1,1′-bi-2-naphthol larger and non-axisymmetric patterns are formed and rotate derivative as a photoinactive shape-persistent codopant, was continuously and unidirectionally. Both the handedness (evidenced fi by the dashed spirals) and the direction of rotation (marked by solid con ned between two glass slides spaced by a gap smaller than white arrows) depend on the chirality of the starting axisymmetric the pitch of the cholesteric helix. Second-generation molecular pattern. Scale bars, 20 μm. Adapted with permission from ref 452. motors 25 (Figure 33) and 91 (Figure 70) were employed. At Copyright 2018 Springer Nature. low irradiation power, axially symmetric chiral patterns were observed by polarized optical microscopy (Figure 72a). Above a certain irradiation power, structural symmetry breaking took The self-assembly in water of second-generation overcrowded place spontaneously, leading to non-axisymmetric patterns alkene motors rendered amphiphilic by appropriate substituents 456 93 featuring a kink (Figure 72b). The patterns were seen to rotate was investigated by Feringa and co-workers. Compounds and 94 (Figure 73a) form tubular structures when coassembled continuously, with both the handedness and direction of with the phospholipid DOPC, as observed by cryogenic rotation dictated by the axisymmetric pattern from which they transmission electron microscopy. While the nanotubes arose. The unidirectional rotation was attributed to the interplay containing 93 did not exhibit morphological changes upon between the twist of the supramolecular LC arrangement and ff light irradiation, a transition from a tubular shape (nanotubes) the di usion of the chiral molecular motors away from a to a spherical shape (vesicles) was observed upon irradiation of localized illumination area. It was also shown that a particle-like the nanotubes containing 94 as a consequence of the LC structure can orbit around the center of the revolving pattern transformation from the stable E isomer to the unstable Z one when it is trapped in the periphery of the latter. In other words, (Figure 73b). Heating the system induces the isomerization of the light-fueled rotation of the LC is harnessed to move a cargo. fi the molecular motor back to the starting isomer without the A signi cant feature of this assembly is that it can use the energy observation of a change in the morphology of the vesicles. of light to establish and maintain nonequilibrium conditions at However, the original nanotubes are obtained after freeze− length scales that are typically 4 orders of magnitude larger than thawing of the sample. The results indicate that the rotary motor their molecular components. function of 94 is preserved when this compound forms 5.5.2. Self-Assembled Systems. Control over the aggregates in water, thus opening the way to the operation of orientation and mutual alignment of molecules in order to light-driven molecular motors in aqueous media. obtain cooperative effects can be achieved by taking advantage Amphiphilic overcrowded alkene motors were found to of supramolecular association phenomena such as gelation and undergo hierarchical self-organization in water, yielding nano- amphiphilic self-assembly. For example, overcrowded alkene fibers that can be further assembled into aligned bundles that photochromic switches, structurally related to the molecular eventually make up centimeter-long strings.457 Compound 95 rotary motors discussed in section 3.6.1, have been utilized to (Figure 74) resembles amphiphile 94 (Figure 73a) and consists exert photocontrol over solvent gelation processes.453,454 In of a second-generation motor functionalized with a dodecyl another study, an amphiphilic overcrowded alkene switch was chain on the rotor side and two carboxyl-terminated alkyl chains found to self-assemble into vesicles that can shrink in response to on the stator side. The initial stage, self-assembly of 95 in light irradiation and expand upon thermal relaxation.455 Such aqueous NaOH at a concentration of 5% w/w, affords materials are appealing for intelligent drug release or control of micrometer-long nanofibers with a diameter of about 5−6nm biological phenomena.227 (Figure 74a). Spectroscopic studies demonstrated that the

252 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 73. (a) Structural formulas of molecular rotary motors 93 and 94 highlighting their amphiphilic design. (b) Schematic representation of the photochemically and thermally induced changes in morphology of the corresponding self-assembled aggregates. Adapted from ref 456. Copyright 2015 American Chemical Society.

Figure 74. (a) Schematic representation of the hierarchical self-organization of amphiphilic molecular rotary motor 95 into nanofibers and bundles that make up macroscopic soft strings. (b) Structural formula of the molecular motor. (c) Photographic snapshots of a supramolecular string in water during UV irradiation from the left. Bending toward the source from 0 to 90° occurs within 60 s. Scale bar, 5 mm. Adapted with permission from ref 457. Copyright 2017 Springer Nature. photoinduced motor function of 95 is preserved in the self- to the unstable isomer causes an increase in the excluded volume assembled fibers. Manually drawing the fiber solution into a around the motor, which in turn causes a perturbation of the ff concentrated aqueous solution of CaCl2 a orded a noodlelike local packing arrangement. Eventually, the effect of light string of arbitrary length. Because of the electrostatic screening irradiation is that of thickening and shortening the fibers; fl fi of the calcium ions and the shear ow, the nano bers became considering the thickness of the string (∼300 μm) and its optical directionally aligned in the bundles that constitute the string density at the irradiation wavelength (due to the absorbance of (Figure 74a). Remarkably, the string readily bent toward the the motor), the contraction occurs only at the photoirradiated light source upon 365 nm illumination in water (Figure 74c) and ° side of the string, thus causing its bending toward the light returned to its original state after 3 h at 50 C. The process could 457 also be carried out in air on a suspended string, which was shown source. The fact that macroscopic actuation by collection and fi to lift a 0.4 mg piece of paper adhered to its end. In situ small- ampli cation of molecular movements can be achieved under angle X-ray scattering (SAXS) experiments were employed to ambient conditions with a self-assembled system consisting of investigate the photoactuation mechanism. It is hypothesized 95% water is very promising for the realization of mechanically that the photoisomerization of the motor from the stable isomer active soft materials.

253 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

Figure 75. (a) The intermolecular “click” reaction between molecules of 96 yields polymer−motor conjugate 97. (b) Photographs showing the contraction of a piece of gel consisting of 97 swollen with toluene upon UV light irradiation. (c) Schematic representation of the braiding of the polymer chains of 97 caused by the photoinduced rotation of the molecular motor units at the branching points, which results in the shrinkage of the gel. Adapted with permission from ref 460. Copyright 2015 Springer Nature.

5.5.3. Systems with Covalently Linked Molecular that the entangled polymer chains are coiled up because of the Motor Units. The incorporation of molecular machines into light-driven unidirectional rotation of the motor components covalent polymers has been proposed for several years as a (Figure 75c). This interpretation is consistent with the results of promising way to collect and amplify motion from the experiments performed on model compounds obtained by the nanometer scale to the macroscopic scale.434,436,439 Remarkable intramolecular reaction of the arms of 96 (achieved under dilute examples in this regard are polymers obtained by the head-to-tail conditions) to yield eight-shaped macromolecules. AFM connection of [c2]daisy chain rotaxane dimers.458,459 Recent imaging revealed that individual eight-shaped objects exhibit a investigations have shown that the synchronous collective transition to a collapsed, more compact shape under UV mechanical switching between contracted and expanded forms illumination, a result consistent with the motor-driven formation of the monomers, triggered by pH changes432 or light of a wound structure. irradiation,73 can bring about a change in the size of a It is worth noting that this system exploits the unidirectional macroscopic fragment of material. movement of a molecular motor driven autonomously by a Studies of polymers with covalently embedded molecular single stimulus and is therefore substantially different from motor elements are very rare. Giuseppone and co-workers materials based on molecular mechanical switches, which are incorporated second-generation overcrowded alkene rotary interconverted between two thermodynamic minima by differ- − motors into a polymeric gel and investigated the effect of UV ent stimuli.73,429 432,459 As a matter of fact, the continuous irradiation on the resulting material.460,461 Compound 96 photoinduced rotation of the motor units in 97 drives the system (Figure 75a) was obtained by functionalizing the stator and progressively away from thermal equilibrium; the energy of rotor halves of the enantiopure motor with two alkyne- incident photons is thus converted into free energy of the terminated oligomeric ethylene glycol chains and two azide- entangled polymer chains (whose entropy decreases) and stored terminated poly(ethylene glycol) chains, respectively. The in the gel, with an overall estimated efficiency of about 0.15%. successive copper-catalyzed alkyne−azide cycloaddition This energy, however, could not be retrieved because the light- (“click” reaction) performed with 96 under high-concentration driven braiding of the polymer was irreversible. conditions afforded the cross-linked polymer 97 (Figure 75a), in To address this issue, the design depicted in Figure 75 was which the ethylene glycol chains attached to different motors are improved by introducing diarylethene photoswitches in the gel connected together by means of triazole units. The polymer was as “modulator” elements462 that act as on-demand elastic found to form a gel in toluene at 10% w/w, which was releasers by unbraiding the polymer chains in the cross-linked characterized by SAXS and atomic force microscopy (AFM) network. For this purpose, compound 98 (similar to 96 but supported by DFT calculations. The contraction of a millimeter- containing only alkyne ends) was copolymerized with azide- sized piece of the gel caused by UV irradiation could be clearly terminated diarylethene derivative 99 (Figure 76a) to yield a seen (Figure 75b). Such a behavior was explained by assuming polymeric gel analogous to 97 (Figure 75a) containing both

254 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

the motors (Figure 75c) while the diarylethene units are in their closed (locked) form, thereby sustaining the coiling of the polymer chains caused by the motors. Conversely, visible-light irradiation switches the modulators to their open (unlocked) form but is ineffective for actuation of the motors (Figure 76). Free rotation around C−C single bonds in the diarylethene units can thus release the torsional energy accumulated in the braided polymer until thermodynamic equilibrium is reached. It is important to note that the reversibility of the process relies on the elastic properties of the polymer. Upon irradiation with both UV and visible light, the motors coil the polymer chains and the modulators allow their unwinding. By adjusting the relative intensities of the UV and visible light, one can tune the winding and unwinding rates and overall determine whether the gel is contracting or expanding. When these rates are equal, a photostationary out-of-equilibrium state is reached. Hence, the energy stored in the material and its mechanical output can be tuned by optical modulation of the braiding and unbraiding frequencies. As discussed in section 1, unidirectional motion is necessary for a molecular machine to bring its surroundings away from equilibrium; collection and accumulation of the effects of such movements in a material, however, may lead to irreversible changes that prevent the exploitation of the harvested energy (see above). The strategy devised by Giuseppone and co-workers462 provides a general solution to this problem by precise molecular design and paves the way toward the development of more complex molecular- motor-based systems capable of converting light energy into potential and mechanical energy.

6. CONCLUSIONS AND OUTLOOK After billions of years of evolution, nature has managed to produce amazingly beautiful and sophisticated molecule-based motors that oversee the most important aspects of the operation of living organisms. In a few decades, chemists have learned how to design, synthesize, and activate artificial molecular motors, thus fulfillingat least in partFeynman’sprophecyon nanotechnology.12 Although human-made molecular machines and motors cannot rival biological ones in terms of functionality, efficiency, and structural complexity, much progress has been made from both theoretical and experimental standpoints. The research in this field has evolved from an initial stage in which scientists were sharpening their wits to build simple prototypes of molecular machines by emulating the structure or movements of macroscopic counterparts to a more mature period in which researchers have gained more awareness of the fundamental concepts at the basis of nanoscale motion and begun to focus on issues such as energy supply, directional control, and interaction Figure 76. (a) Structural formula of alkyne-terminated molecular with the environment. The amazing growth of this area is rotary motor 98. (b) Structural formula of the diarylethene-based “ ” evident also from a quantitative point of view if one considers the compound 99 that by a quadruple intermolecular click reaction with fi 98 yields a cross-linked polymer similar to 97 (Figure 75a) containing increase in the number of books, articles, and scienti c meetings both molecular motor and modulator units. The open form (modulator in the subject. More and more scientists are eager to tackle the unlocked; rotation axes shown in gray) and closed form (modulator many challenges related to the utilization of artificial molecular locked) can be interconverted by UV and visible-light irradiation. (c) machines to perform tasks and ultimately their exploitation in Schematic representation of the gel obtained by copolymerization of 98 the real world. In fact, the 2016 Nobel Prize in Chemistry and 99 and of the UV-induced braiding and visible-light-induced recognized not only the huge and largely unexplored applicative unbraiding of its chains. Adapted with permission from ref 462. potential of these tiny devices but also the very significant Copyright 2017 Springer Nature. conceptual and technical leaps forward achieved in chemistry and neighboring disciplines by applying an engineering modulator and motor subunits. A key feature of this design is mentality, synthesis-driven creativity, and bioinspired ingenuity that the modulators can be activated at a wavelength different to molecular sciences. from that employed to operate the rotary motors. In particular, In the context of molecular motors, the development of irradiation with UV light promotes the unidirectional rotation of systems driven by light- or redox-induced processes is

255 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review particularly interesting because while the vast majority of stimuli (other than the energy source) is an important biomolecular motors are powered by chemical reactions, the use step forward toward the realization of adaptive systems of photonic or electrical stimuli is more appealing from a that can dynamically respond to environmental changes. technological perspective. As illustrated by the examples in this It may be envisaged, for example, that molecular motors review, the evolution from proof-of-principle designs to more could adjust their working mode according to a given advanced prototypes has led to the construction of artificial combination of substrates (i.e., to the result of a logic molecular motors capable of exploiting an energy source operation between them) or that self-regulating nano- autonomously to produce directional motion that through mechanical devices could be constructed by implement- judicious interfacing of the motor with its surrounding ing feedback loops within their operating mechanism. The environment can be used to accomplish a function. Never- sporadic examples of stimuli-gated autonomous light- theless, analysis of the state of the art of photo- and redox-driven driven molecular motors described in section 3.6.1 are a molecular motors also highlights that there are still several gaps good starting point, but more research is required to reach to be filled, problems to be solved, and challenges to be faced. In the above-mentioned goals. the following we try to identify the most significant issues that in • Taking full advantage of directed motion. In several our opinion should be addressed in the near future; many of examples described in section 5, molecular rotary motors them are not necessarily limited to redox- and photoactivated are employed as bistable photoswitches or, at best, as systems. multistate switches. In these cases, the task performed by • Expanding the variety of molecular architectures. Most the motor does not arise from the oriented sequence of of the molecular rotary motors developed to date are transitions between states that leads to unidirectional ff based on a single class of molecules, and some types of motion. On another front, the potential e ect of relative devicesfor example, redox-driven rotary motors based directional transport of one molecular component with on catenanesare still missing. The construction of respect to another vanishes if they eventually dissociate in fl linear motors capable of directed long-range translation is a homogeneous uid medium. Thus, although supra- at a very early stage. Thus, promoting fundamental molecular pumps capable of directional and autonomous research on new types of molecular motors is essential to light-driven motion are available (section 3.3), they need strengthen the scientific ground of the field and enrich the to be introduced in compartmentalized environments to “toolbox” available to “molecular machinists”. While take advantage of the active transport. In general, from a synthetic minimalism for motor modules is surely a functional point of view there is much to be gained from plus, modern chemical synthesis can indeed be called to the full exploitation of directed movements, particularly arms for incorporating the motors into large and with regard to the conversion and storage of the energy sophisticated architectures. inputs. • • Connecting active and passive molecular mechanical Precise mechanistic and operational understanding. parts. Macroscopic machines usually comprise a motor Detailed knowledge of the processes at the basis of the ff component that drives passive moving parts such as gears, operating mechanism and the way they are a ected by the chains, and shafts. A similar situation can be envisioned environment (temperature, solvent/matrix, presence of for future nanomechanical devices. The construction of counterions and other species, etc.) is not always available artificial multicomponent systems in which molecular for the systems reported to date. This information is motors are mechanically coupled with other movable particularly important for the thoughtful design of new molecular-level parts is a fascinating and delicate task. The generations of motors. Moreover, investigating the transmission of motion requires a fine balance of the steric thermodynamic and kinetic aspects of the working cycle interactions: if the fit is too tight, the device is blocked, but of a motor is essential to assess its ability to function away if it is too loose, the coupling is lost. Recent proof-of- from thermodynamic equilibrium and identify appro- principle studies aimed at combining molecular rotary priate operational conditions. To advance in this ff motors with passive rotors or pistons (section 5.2) have direction, a strong e ort in terms of high-level paved the way for further investigations. physicochemical experimental and computational techni- • Single-molecule operation. The realization of molecular ques is required. machines that can be operated and monitored individu- • Autonomous exploitation of the energy source. This ally at the nanometer scale is one of the most thrilling and feature, which enables the motor to repeat a working cycle imaginative goals of nanoscience. Besides the construc- by continuously dissipating energy from a single source tion of “nanocars”, such an objective is also relevant for rather than requiring an operator-dependent sequence of high-density data processing and storage.172 The main different inputs, is crucial for practical operation. This is problems are the identification of appropriate supports how motor proteins operate, by constantly consuming typically, surfacesto afford a desired degree of (im)- ATP as a fuel. Artificial molecular motors that dissipate mobilization of the molecular machines and the solution light energy in an autonomous manner are available, but to the technical difficulties related to excitation/ they belong to a restricted category of chemical addressing and imaging/readout at the single-molecule compounds. For example, autonomous light-fueled level. catenane rotary motors have not been realized yet, and • Harvesting collective effects. Natural systems show that autonomous operation of redox-driven molecular ma- macroscopic work can be performed by harnessing the chines has not been achieved. motion of many molecular motors that are appropriately • Advanced regulation of the motor activation. The organized in space and operated synchronously. Indeed, construction of molecular motors whose operation can be the amplification of movement from the nanometer world turned on/off or modulated by physical or chemical up to larger scales requires the arrangement of artificial

256 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268 Chemical Reviews Review

molecular machines with a controlled orientation into an activity is focused on the design and characterization of artificial extended framework. From an operational viewpoint, molecular machines based on interlocked structures, photochromic such a structure should not only preserve the motion but compounds and photoactive molecular materials, and complex systems also enable the parallel stimulation of large number of for signal processing. individual devices. Although recent attempts based on Alberto Credi is Professor of Chemistry at the University of Bologna both soft matter (liquid crystals, supramolecular poly- and an associate research director at the National Research Council. He mers, and covalent gels; see section 5.5) and hard matter is the founder and director of CLAN. His research deals with the (covalent frameworks; see section 3.6.1) are promising, development of stimuli-responsive molecular-based systems, with a the preparation and characterization of hybrid materials of ffi particular focus on logic devices, machines, and motors. He has this kind remain considerably di cult tasks. authored four books and over 280 scientific publications, and he is the fi In conclusion, research on photo- and redox-driven arti cial principal investigator of an Advanced Grant of the European Research molecular motors, despite its relatively young age, is Council for the development of light-driven molecular motors. Since characterized by a past of exciting discoveries, a present of the beginning of his career he has been engaged in the popularization of outstanding achievements, and a future of astonishing challenges chemistry disciplines and scientific culture in general. for both fundamental and applied science. Indeed, constructing functional devices and materials based on artificial molecular motors is an extremely complex endeavor. Nevertheless, these ACKNOWLEDGMENTS systems have the potential to revolutionize entire sectors of Financial support from the European Union’s Horizon 2020 technology and medicine by disclosing radically innovative research and innovation program (ERC Advanced Grants solutions to problems in fine chemistry, solar energy conversion “Leaps” 692981 and FET-OPEN “Magnify” 801378) and the and storage, information and communication technology, Ministero dell’Istruzione, Universitàe Ricerca (FARE Grant medical diagnostics and therapy, robotics, etc. The opportunity “Ampli” R16S9XXKX3) is gratefully acknowledged. to go well beyond the incremental improvement of existing fi paradigms to address key societal challenges justi es the high REFERENCES risks and long times inherent to this research and motivates more and more scientists to join it. (1) Mann, S. 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268 DOI: 10.1021/acs.chemrev.9b00291 Chem. Rev. 2020, 120, 200−268